Clinical trial NCT01911676
Conditions: Cognitive Impairments Associated With Schizophrenia
Sponsor: Yale University
Start date: 2013-08-01; Completion date: 2018-12-01
Enrollment: 71 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This is a Phase II, randomized, double-blind, placebo-controlled, cross-over POC study of stable patients with Schizophrenia or Schizoaffective disorder. The primary objective of this study is to test the efficacy of treatment with one of two does of a glycine transporter inhibitor (GlyT1I) combined with cognitive remediation to enhavce cognitive function. Subjects will be randomized to one of two doses of the glycine transporter inhibitor (GlyT1I) and placebo twice daily in addition to their antipsychotic medication for 2 treatment periods, each lasting a minimum of 5 weeks. Treatment periods will be separated by a washout period lasting approximately 3 weeks.

Detailed description:

Arms: arm 1: Active dose between 40mg arm 2: Active dose between 60mg arm 3: Placebo- no active dose of PF-03463275.
Interventions: intervention 1: PF-03463275 intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
ICF_002.pdf: 
NCT01911676 
Translational Neuroscience Optimization of GlyT1 Inhibitor 
 
Consent Form – Approved by IRB on 7/12/2018 


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COMPOUND AUTHORIZATION AND CONSENT FOR PARTICIPATION IN A 
RESEARCH PROJECT
YALE UNIVERSITY SCHOOL OF MEDICINE – YALE-NEW HAVEN HOSPITAL
YALE UNIVERSITY SCHOOL OF MEDICINE—CONNECTICUT MENTAL HEALTH 
CENTER
Study Title: Translational Neuroscience Optimization of GlyT1 Inhibitor
Principal Investigator:  Deepak Cyril D’Souza, M.D. 
Funding Source: National Institutes of Health, National Center for Advancing Translational 
Science
Sub-study 2: Patients with Schizophrenia or Schizoaffective Disorder
Invitation to Participate and Description of Project
You are invited to take part in a research study designed to test a new potential 
investigational medication for treating schizophrenia. An investigational drug is one that has not 
been approved for sale by the United States Food and Drug Administration (FDA). The 
medication is called PF-03463275 and it has been thoroughly tested for safety in human subjects. 
This medication interacts with a receptor in the brain called the NMDA receptor and may reduce 
cognitive deficits.  This study will also compare the effects of PF-03463275 with a placebo to 
see if taking PF-03463275 is better than taking placebo.  Placebo is a capsule that looks like PF-
03463275 but has no drug in it.  In this study we are testing this medication’s effects on thinking 
and cognition in patients with schizophrenia or schizoaffective disorder as described below. 
You have been asked to participate because you have been diagnosed with schizophrenia 
or schizoaffective disorder and you are currently being treated with an antipsychotic, except 
clozapine. You have not required inpatient hospitalization for at least 3 months prior to screening 
and you are not addicted to drugs or alcohol. Despite this treatment, you may still be 
experiencing difficulty with your cognition.  Cognition is the way people think, and it includes 
abilities like paying attention, focusing, remembering things, and solving problems. 
Over the phone, you were asked a series of questions about psychiatric and medical 
symptoms that you may have experienced during your lifetime. These questions were used to 
determine whether you were likely to meet study requirements. Since the results of this 
telephone-screening interview indicated that you may qualify for this study, we have invited you 
for an additional set of interviews and lab tests requiring an outpatient visit to the Connecticut 
Mental Health Center (CMHC), Clinical Neuroscience Research Unit at 34 Park St. New Haven, 
CT. 
In order to decide whether or not you wish to be a part of this research study you should 
know enough about its risks and benefits to make an informed decision.  This consent form gives 
you detailed information about the study, which a member of the research team will discuss with 
you.  This discussion should go over all aspects of this research: its purpose, the procedures that 
will be performed, any risks of the procedures, and possible benefits.  Once you understand the 
study, you will be asked if you wish to participate; if so, you will be asked to sign this form.  
Please note that you will be told of any significant new findings that are developed during the 
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course of your participation in this study that may affect your willingness to continue to 
participate.
Description of Procedures
If you agree to participate in this study, you will complete a screening session.  If we feel 
this study is appropriate for you, we will schedule you for a baseline visit and 2 study periods. 
Each study period will last a minimum of 5 weeks, and will be separated by a washout lasting 
approximately 3 weeks. During each of your study periods you will be randomly assigned to take 
placebo or active PF-03463275 twice daily in addition to your antipsychotic medication. During 
the week that you take active PF-03463275, you will be randomly assigned to take either a 40 
mg dose or a 60 mg dose. Neither you nor the study doctor and the research clinic staff, who 
work with you, will know which pill you are taking. You will begin taking study medication 
during the first week of each study period, and you will be assessed for side effects and will meet 
with research staff and a study doctor. If the first week of taking the study medication goes well 
you will begin cognitive remediation training that will last for approximately 4 weeks. The 
cognitive remediation training will require you to come to a computer lab at the West Haven VA 
for approximately 5 hours each week.
Each treatment period may be extended by up to 14 days, to provide scheduling flexibility in 
extenuating circumstances, which would obstruct your progress in the study, such as 
departmental closings and scheduling conflicts.
The study periods will be separated by a “washout period”, which must last approximately 21 
days. The study period extensions will allow for scheduling flexibility for circumstances in 
which you require more than the standard amount of time to complete study procedures. 
In extenuating circumstances, for ease of participation, you may be given the opportunity to stay 
overnight at the Connecticut Mental Health Center (CMHC) located at 34 Park Street, New Haven, CT or 
at a hotel close to the CMHC for a portion of your participation at the Principal Investigator’s discretion, 
so that you do not have to travel back and forth from home.  In the event that you do stay at the CMHC, 
you will engage in routine admission procedures on which include evaluation by both a doctor and a 
nurse, a physical examination, measurement of height and weight, vital signs, ECG, and routine clinical 
laboratory tests. You will not receive any additional compensation for any overnight stays.  Your 
compensation will occur as described in the Economic Considerations section.  
Screening 
The study will begin with two screening visits that will take place at CMHC, 34 Park 
Street, New Haven, CT. The purpose of the screening visit is to find out if you meet all of the 
requirements to take part in this research study. Before any study-related procedures are 
performed, you will be asked to read and sign the informed consent, if you wish to participate. 
The following tests and procedures will be performed to determine if you qualify: 

Review of your medical, surgical and psychiatric history 

Review of your current and past medications (prescription, non-prescription, and 
dietary supplements) 

Physical examination 
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
Measurement of your height, weight, and vital signs (blood pressure, heart rate, 
respiration rate and temperature) 

Completion of questionnaires related to your current diagnosis of schizophrenia and 
suicidal thoughts/behaviors 

Electrocardiogram (ECG - a test that measures the electrical activity of your heart)

Genetic testing:  A small sample of your blood (about a tablespoon) will be taken for 
genetic analysis.  Genes are the structures inside your cells that were passed to you 
from your mother and father, that make you more like your relatives than like 
strangers. The genes provide the “blueprints” or “plans” your cells follow as they 
make proteins, which in turn are the building blocks for your body and brain. DNA is 
the chemical that makes up genes. In this study, we will test for the gene of a 
particular enzyme that metabolizes the study medication. This is a part of screening 
for this study. In addition, we will want to look at your blood to learn if your genes 
affect your response to the study drug. We plan to keep your DNA samples 
indefinitely (as long as possible) in the laboratory and they may be used for other 
analyses that will allow us to better understand cognitive function and psychiatric 
illnesses in the future.  These analyses may include information regarding other 
things that you tell us about yourself or that we learn about you in the course of this 
project.  Your identity will be carefully guarded.  We may study many different genes 
in the course of this research, and will retain the DNA sample in the laboratory 
indefinitely. 

Laboratory tests including: 
o
Tests for hepatitis B, C and HIV/AIDS. Positive HIV, hepatitis B, or C results 
will be reportable to the Connecticut Department of Public Health. 
o
Pregnancy testing for women who are able to become pregnant. The result of 
the pregnancy test must be negative for you to qualify to participate in this 
study 
o
Routine Urine analysis
o
You will be asked to breathe into a device called a breathalyzer that will 
measure your blood alcohol content
o
Drug testing for illegal drugs of abuse. You will not be allowed to participate 
in this study if you test positive for illegal drugs 
 If you have completed a prescreening visit, relevant assessments may be incorporated in to the 
screening for this study with your permission.
You will undergo a detailed psychiatric and physical evaluation with a doctor. 
Additionally you will be asked to complete a few tasks measuring thinking, memory, attention 
and perception. All these procedures will take approximately 4 hours.  
If you do not fit study requirements, you may be excluded from the study. In that case we 
will discuss with you the findings and will advise you about appropriate follow-up. In this case 
you cannot participate in further study visits and you will be discharged from the study.
Study Periods  
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If you are found to be eligible after the screenings, you will be scheduled for the Baseline 
visit and 2 study periods. Each study period will last a minimum of 5 weeks, and will be 
separated by a washout lasting approximately 3 weeks. During each of your study periods you 
will be randomized to either PF-03463275 or placebo. During the study drug phase of the study 
we will schedule a time for you to come to the Learning Based Recovery Center (LBRC) at the 
West Haven VA for cognitive remediation training for up to 5 hours a week for approximately 4 
weeks per study period.  We will also schedule weekly visits at the Connecticut Mental Health 
Center to monitor how you are doing. The study periods will be separated by a “washout period”, 
which must last approximately 21 days, but may be extended per the discretion of the PI. 
During study participation, you will be required not to drink grapefruit juice and not to 
take certain medications that may interfere with the study medication. All your current 
medications will be reviewed at each visit. You will also be asked to provide blood and urine 
samples for routine lab tests to check on your health, and to test for alcohol, and drugs of abuse. 
Women of childbearing potential will have urine pregnancy tests throughout the study.  You will 
have evaluations that will include physical and psychiatric examinations, vital sign 
measurements and ECGs. You will be asked to answer questions about your schizophrenia 
symptoms and daily activities. Also, at these visits, we will measure your heart rate, blood 
pressure and respiration and give you the study medication. You will take the study medication 
each morning and evening for the entirety of each dosing period. Though we do not expect any 
difficulties, we will provide you with a 24-hour phone number so you can reach a physician if 
you have concerns about the medication at any time. Your total participation in this study will 
last approximately 16 weeks.
Your compliance to the study medication will be monitored by weekly self-report and pill 
counts at study visits and using the Cellphone Assisted Remote Observation of Medication 
Adherence (CAROMA) method. This is basically a method that allows us to confirm that you are 
taking the study medication visually using the camera of a cellphone. CAROMA may be used 1 -
2 times per day during the treatment period to confirm compliance. Flexible scheduling will be 
maintained regarding time and days of CAROMA depending on your availability and frequency 
of in person visits.  This will only occur on weekdays.  You will be provided with a cellphone 
with the hardware, software and service necessary to video. The phone will have service that is 
restricted. Prior to beginning study medication (PF-04457845 or placebo), you will be trained 
how to use the phone and also trained on the protocol for doing the compliance checks. For this 
training, you will be placed in one office with the phone. A research staff member will video call 
you from another location in the clinic and observe you consuming one M&M candy with a glass 
of water. Once successfully trained in the clinic, you will be loaned the phone to take home for 
one trial visit. This is to ensure that 1) you understand how to use the phone and 2) that you have 
adequate cell service at home.
If you have demonstrated that you understand how the video calling works, you will be 
called during the week while you are taking the study medication at a predetermined time. You 
will be observed removing study medication from the packaging and swallowing the medication 
with water. In addition, we will also ask you how you are feeling since you have started the study 
medication.  You will receive additional compensation for CAROMA visits which is outlined in 
the “Economic Considerations” section. If you are not contactable, it will be assumed that you 
have been noncompliant and will not receive payment for CAROMA visits. At the end of the 
study, you will receive a return fee for returning the phone to us.
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EEG Session
In addition to the assessment procedures described above, you will be asked to participate 
in electroencephalographic (EEG) recording sessions. EEG measures your brain waves, and we 
use it to try to understand how the brain processes information in different situations. You will 
first be fitted with a nylon cap, to which sensors used for EEG recording will be attached. The 
sensors do not make direct contact with your scalp. To make this connection, a gel is inserted 
through holes in the cap.
This gel is made for this purpose and can easily be washed out of your hair with warm 
water after the experiment. You will be seated in front of a video display in a dimly lit recording 
room, and asked to wear foam insert earphones. During EEG recording you will be asked to view 
images on the video display. These images are simple shapes, including a circle and a square 
checkerboard, and they will be presented at different rates in two conditions. In one condition 
you will be asked to press a button on a keypad to certain images and to withhold the button 
press to others.  In another condition one of these images will be shown very quickly, so that it 
appears to “flicker” on and off. Under this condition you will only be asked only to look at the 
flickering image, and will not need to press any buttons. In another condition you will be asked 
to memorize short lists of letters. The EEG recording sessions, including set up time and 
experiments, will take approximately 90 minutes each.
Cognitive Remediation 
All participants will have the opportunity to receive computer-based cognitive training 
using commercially developed software. A series of exercises involving attention, memory, and 
processing speed skills will be combined over individual sessions lasting a minimum of 
approximately 45 minutes and a maximum of approximately 2 hours, depending on your 
schedule preference. We ask that you complete 5 sessions over each 4 week training period.  We 
recommend a schedule of 1-2 training sessions per day, 3 to 5 days per week. You will 
participate in approximately 40 sessions over the course of the study. The program will instruct 
you on what exercises to use and how to do them. Generally the more you practice these 
exercises the better you get at them, so a consistent training schedule is encouraged for best 
results. Cognitive training will be completed at a monitored computer laboratory located at VA 
Connecticut (Bldg 14), which will be available to you from approximately of 10:00 am to 12:00 
pm each morning and from approximately 1:00 pm to 3:00 pm in the afternoon. This schedule 
will regularly be maintained Monday through Friday, unless in extenuating circumstances. No 
prior computer experience is necessary, an assistant will be available to help answer your 
questions as needed. We will make every effort to create a schedule that is most convenient to 
you and that does not interfere with work or other activities. 
It is important for you to know that that there is a new law in Connecticut (Public Act 13-
3), that may affect you if you participate in this study. The law requires hospitals to report to the 
Department of Mental Health and Addiction Services (DMHAS) the names of all persons who 
are voluntarily admitted for psychiatric care. Under the law, DMHAS will report to the 
Department of Emergency Services and Public Protection (DESPP) the names, addresses, 
birthdates and social security numbers of all persons who are voluntarily admitted and who are 
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registered gun owners or who apply for a gun registration within six months of admission. The 
DESPP will revoke the gun permit, confiscate the gun and deny new permits for six months after 
the admission. You will be affected by this law only if you legally own a gun or are planning to 
register for one in the next six months.
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.
You will be told of any significant new findings that are developed during the course of your 
participation in this study that may affect your willingness to continue to participate.
Risks and Inconveniences 
There may be side effects that are not known at this time. You will be told of any 
significant new findings that are developed during the course of your participation in this study 
that may affect your willingness to continue to participate. 
Possible risks from participation in this study include: 
• Risks associated with blood drawing 
• Risks associated with cognitive remediation 
• Risks associated with electroencephalography (EEG)
• Risks associated with the study drug 
• Risks associated with any medication
• Risks associated with genetic testing
• Risks to embryo, fetus and nursing infants 
Risks associated with blood drawing: Drawing blood and inserting an intravenous line (IV) into 
an arm vein are safe and standard medical procedures. Sometimes a bruise will occur at the 
puncture site and rarely a blood clot or infection will occur in the vein. You should not donate 
blood for at least eight weeks after the study. The total volume of blood collected during this 
study will be up to 36 tablespoons, including blood drawn for the screening and blood drawn 
during the dosing period. This amount of blood is much less than the amount of a typical 
donation to a blood bank. 
.
Risks from Cognitive Remediation: There are no known physical risks associated with 
computer-based cognitive remediation. Fatigue and frustration during training are possible. If 
this occurs, you will be encouraged to take breaks, during which you can drink coffee or halt 
training for the day. Research staff will monitor you during training and may advise you to seek 
further treatment if symptoms worsen as a result of participation in the study.
Risks of EEG Testing: There are minimal risks associated with EEG/ERP recording. A 
conductive gel is applied, which can be easily washed out of your hair with warm water. A 
shower facility for hair washing and sterile linens are available in the laboratory. Electrode caps 
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and sensors will be washed and sterilized between subjects to minimize the risk of transmitting 
infection.
Risks from the administration of Study Medication PF-03463275: To assure your safety, we 
will thoroughly screen you medically and will check your pulse, blood pressure, and respiration 
on each study visit. We will also conduct a detailed psychiatric examination and ask about your 
symptoms at each telephone or in-person visit. In addition, we provide a 24 hour number so you 
can contact the study doctor at any time if you become concerned. Your total participation in this 
study will last approximately 16 weeks.
The study medication (PF-03463275) has been tested for safety and has been used in a 
number of clinical trials in healthy subjects and in two separate studies in patients with 
schizophrenia.  In one study, patients with schizophrenia received doses of 5 mg- 25mg every 6 
hours for 1 week. These doses were well tolerated with no serious adverse events related to the 
study medication. In a separate study patients with schizophrenia received 30 mg twice daily for 
1-12 weeks. Patients tolerated the medication well overall. The most common side effects 
(>10%) reported in both these studies included headaches, sleepiness or less sleep, dry mouth 
and increased urination. Less common side effects (1-10%) included dizziness, restlessness, 
thirstiness, palpitations, blurry vision and flashing lights, nausea and stomach problems. One 
patient experienced high heart rate and decreased blood pressure but this resolved on its own. In 
the previous study done here at Yale, 20 mg twice daily, 40 mg twice daily and 60 mg twice 
daily were tested, and were very well tolerated. In addition to the above listed side effects, you 
may also experience increased anxiety or a worsening of your psychiatric symptoms. In case of 
worsening of your symptoms, we may ask you to come in for an evaluation with the study 
doctor. If needed, for your safety, you may be escorted to an emergency room for an evaluation 
and even admitted to an inpatient unit.  
General Risk of Allergic Reaction: Any drug, including PF-03463275, may cause allergic 
reactions. Allergic reactions can become serious and require immediate treatment in a hospital or 
emergency room. If you have a very bad allergic reaction, you could die. Some things that can 
happen during an allergic reaction that could be a sign or symptom of a life-threatening allergic 
reaction (anaphylaxis) are: 
• rash 
• hives 
• having a hard time breathing 
• wheezing sounds when breathing 
• sudden drop in blood pressure (making you feel dizzy or lightheaded) 
• swelling around the face, mouth, lips, throat or eyes 
• fast pulse 
• sweating 
You should get medical help and notify the study doctor or study staff immediately if you have 
any of these or any other side effects during the study. You will be checked regularly for any 
symptoms and will be treated for them as needed. If your study doctor feels that there are any  
problems, you will be withdrawn from the study and followed by the study doctor for the 
necessary time period.
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Risks Associated with Genetic Testing: Under some circumstances, it can be a risk for genetic 
information about you to be known. Variation in some genes is known to be directly related to 
risk for certain illnesses, and other genes we may study in your DNA may be shown at some 
point in the future to be related to illness. The results obtained from the research that involve 
your DNA sample will not be given to you or the study physician. These test results are for 
research only. The DNA test results will not be put in your medical records. (If you want to 
know your risk for genetic diseases, we will refer you to a genetic counselor.) Additionally, the 
biological materials that we collect from you will be identified by code number rather than by 
name to maintain confidentiality. We hope that this will prevent any information that could cause 
you trouble in the future from becoming known to anyone other than the scientists working on 
this study. We believe that the chance of this information becoming known to others in such a 
way that it would be harmful to you is small. 
There is a federal law called the Genetic Information Nondiscrimination Act (GINA). In 
general, this law makes it illegal for health insurance companies, group health plans, and most 
employers, except those with less than 15 employees, to discriminate against you based on your 
genetic information. However, it does not protect you against discrimination by companies that 
sell life insurance, disability insurance, or long-term care insurance 
Your genetic data and relevant clinical information may be submitted to the National 
Institutes of Health (NIH) Genome-Wide Association Studies (GWAS) database where it can be 
used for future research. All data will be de-identified and will not carry any identifiers prior to 
submission. With your permission, the research data collected in this database will be used by 
qualified researchers to study the genetic basis of psychosis, and other diseases. All information 
will be de-identified prior to submission to the NIH GWAS and/or other restricted-access 
scientific database. De-identified means that the researchers will use your information without 
knowing your identity. The genetic data that you have donated for this research study may be 
sent to the NIH GWAS (and/or other restricted-access scientific database) and may include the 
following information about you: [ age at sample collection, gender, race]. 
In addition to the referenced risks, there is the possibility that unforeseeable risks could 
occur as a consequence of your participation in this study, from the study drug PF-03463275,
Reproductive Risks:
Men: If you are a man, you must be either surgically sterile (vasectomy), sexually inactive, or 
agree to using a barrier method (condom) of birth control from the time of the Screening Visit 
through the end of the Follow-up Period. 
Women: If you are a woman, you cannot be in this study if you are pregnant, planning to become 
pregnant during the study or nursing a child. 
If you are able to become pregnant, you must agree to use a double barrier method of birth 
control from the start of the Screening Period through the end of the Follow-up Period: 
1. Physical barrier (such as condoms or intrauterine device [IUD]), and 
2. Chemical barrier (such as birth control pills, spermicidal jellies or foams). 
A diaphragm must be used with spermicidal jelly or foam. The combination of a diaphragm 
and spermicidal jelly or foam counts as a single barrier. Ask the study doctor if you have 
questions about the birth control requirements of the study. Some methods of birth control will 
not work while you are taking certain drugs. 
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If you are pregnant or nursing a child while taking PF-03463275, there may be risks to your 
unborn baby or nursing child. Nobody knows what these risks are right now. Some drugs cause 
women to have their babies prematurely (early) or to have babies with birth defects.
Benefits 
You may or may not receive any direct medical benefit from being in this study. 
However, information learned from this study may help us to better understand the biological 
bases of memory and to develop more effective medications for people with schizophrenia. Your 
condition may get better, it may get worse, or it may stay the same.  
Economic Considerations

The total amount that you may be compensated is $1,555 if you participate in the entire 
study.

In addition to the compensation for each in-person visit, subjects will be compensated $5 
for completing each compliance monitoring or CAROMA visit by phone. CAROMA 
visits will only be completed on weekdays that the research clinic is open. Subjects may 
earn up to $350 dollars for completing all possible CAROMA visits.

You will receive compensation only for study visits that you attend.

Payments for screening, baseline and week 1 will be made in cash.  All other payments 
will be made via check or debit card unless otherwise requested by the subject or 
subject’s conservator and agreed upon with the P.I. of the study.

After your first payment milestone you will receive your Bank of America pre-paid debit 
card in the mail.  You will need to activate the card over the phone. Any subsequent 
milestones payments will automatically add additional funds to your card. 

To encourage participation in cognitive training, additional incentive payments will be 
dispensed for cognitive training activity, amounting up to $440. Training will be 
administered over approximately 8 weeks, during which you will be asked to complete 
approximately 5 sessions per week, for a total of about 40 sessions. Incentive payments 
will be earned in blocks of 5 sessions, and dispensed according to the schedule outlined 
in the Economic Considerations Table. A maximum of 5 sessions can be completed each 
week, and no additional incentive payments will be made after 40 training sessions. A 
partial payment may be made at the final training session based on the percentage of 
training you complete toward the next payment point. 

All study procedures and medication will be provided free of charge.  There will be no 
costs to you as a part of this study.  
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Confidentiality
Any identifiable information that is obtained in connection with this study will remain 
confidential and will be disclosed only with your permission or as permitted by U.S. or State 
law.  Examples of information that we are legally required to disclose include abuse of a child or 
elderly person, or certain reportable diseases. Information that contains your identity will be 
stored in a locked file on a locked unit or be password-protected on a computer.  To protect your 
privacy, DNA samples will be labeled with a numeric code.  Information linking this numeric 
code with your identity will be stored in a site separate from that where your DNA is stored.  The 
geneticist and other personnel who work with DNA will have no access to any information that 
personally identifies you.  
When the results of the research are published or discussed in conferences, no 
information will be included that would reveal your identity unless your specific consent for this 
activity is obtained.  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.
NCATS Sub-study 2 Economic Considerations
Sub-study 2Visit
Amount
Method
Screening Visit 1
$25
Cash
Screening Visit 2
$25
Cash
Baseline
$75
Cash
Period 1
Week 1
$75
Cash
Week 2
$100
Debit Card
Cog Rem-Session 5 
$20
Debit Card
Week 3
$100
Debit Card
Cog Rem- Session 10
$30
Debit Card
Week 4
$100
Debit Card
Cog Rem- Session 15
$40
Debit Card
Week 5
$100
Debit Card
Cog Rem- Session 20
$50
Debit Card
Washout Week 1
$20
Debit Card
Washout Week 2
$20
Debit Card
Period 2
Week 9
$100
Debit Card
Cog Rem- Session 25
$60
Debit Card
Week 10
$100
Debit Card
Cog Rem- Session 30
$70
Debit Card
Week 11
$100
Debit Card
Cog Rem- Session 35
$80
Debit Card
Week 12
$100
Debit Card
Cog Rem- Session 40
$90
Debit Card
Follow- Up
$75
Debit Card
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If you decide to be in this study and you will be visiting the Connecticut Mental Health 
Center (CMHC) as part of your study procedures, some information about your participation in 
this research study will become part of your CMHC medical record. If you do not already have a
medical record at CMHC, one will be made for your visit. The information that will be entered
into your medical record will include the following: medical and psychiatric history, consent
form, screening procedures, progress notes, nursing notes, lab test results, and results from
physical exams.
We understand that information about you obtained in connection with your health is 
personal, and we are committed to protecting the privacy of that information.  If you decide to be 
in this study, the researcher will get information that identifies you and your personal health 
information.  This may include information that might directly identify you, such as your name 
and telephone number.  This information will be de-identified at the earliest reasonable time after 
we receive it, meaning we will replace your identifying information with a code that does not 
directly identify you. The principal investigator will keep a link that identifies you to your coded 
information, and this link will be kept secure and available only to the PI or selected members of 
the research team. Any information that can identify you will remain confidential.  The research 
team will only give this coded information to others to carry out this research study. The link to 
your personal information will be kept for ten years, after which time the link will be destroyed 
and the data will become anonymous. The data will be kept in this anonymous form indefinitely.
The information about your health that will be collected in this study includes:

Research study records

Medical and laboratory records of only those services provided in connection with this 
Study.

The entire research record and any medical records held by the Connecticut Mental 
Health Center

The following information: Physical examination, results of blood and urine tests 
(including results of the testing for alcohol, tobacco, drugs of abuse, and communicable 
diseases, as well as genetic testing), questionnaires and evaluations, ECG’s, and other 
tests and procedures you have as part of the study.

Records about phone calls made as part of this research

Records about your study visits

Records about any study drug you received
Information about you and your health which might identify you may be used by or given to:

The U.S. Department of Health and Human Services (DHHS) agencies

Representatives from Yale University and the Human Investigation Committee (the
committee that reviews, approves, and monitors research on human subjects), who
are responsible for ensuring research compliance. These individuals are required to
keep all information confidential.

Those individuals at Yale who are responsible for the financial oversight of research
including billings and payments

The Principal Investigator: Deepak D’Souza, MD

The Yale institutional review board

The U.S. Food and Drug Administration (FDA) This is done so that the FDA can
review information about the new drug product involved in this research. The
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information may also be used to meet the reporting requirements of drug regulatory
agencies.

Drug regulatory agencies in other countries

Governmental agencies to whom certain diseases (reportable diseases) must be reported

Health care providers who provide services to you in connection with this study.

Laboratories and other individuals and organizations that analyze your health
information in connection with this study, according to the study plan.

Co-Investigators and other investigators involved in this study, including but not limited 
to  Dr. Mohini Ranganathan, Dr. Morris Bell, Dr. Naomi Driesen, Dr. Jason Johannesen 
and Joshua Kenney

Study Coordinator and Members of the Schizophrenia Neuropharmacology Research 
Team

Data and Safety Monitoring Boards and others authorized to monitor the conduct of
the Study
If as part of the study, transportation (i.e. cab), overnight stay,  or other services are 
provided or paid for by the study, your name will need to be released to the company 
in order to provide services. In addition, part of your compensation in this study will 
be provided via a Bank of America pre-paid debit card. To issue the debit card and 
receive your ePayments for the research procedures you complete, your name, address, 
and telephone number will be shared with Bank of America.
Some of the individuals or agencies listed above may not be subject to HIPAA and therefore may 
not be required to provide the same type of confidentiality protection. They could use or disclose 
your information in ways not mentioned in this form. However, to better protect your health 
information, agreements are in place with these individuals and/or companies that require that 
they keep your information confidential. 
By signing this form, you authorize the use and/or disclosure of the information described
above for this research study. The purpose for the uses and disclosures you are authorizing is to 
ensure that the information relating to this research is available to all parties who may need it for 
research purposes. 
The information about your health that will be collected in this study includes records of 
your study visits including study interventions, lab results and relevant phone calls. The researchers 
involved in this study have obtained a Certificate of Confidentiality (COC) issued by the 
Department of Health and Human Services.  The COC protects the investigators from being 
forced to release any information in which you are identified, even under a subpoena. The 
protection offered by the COC does not stop the researchers from reporting information about 
suspected or known sexual or physical abuse of a child or older person, or a subject’s threats of 
violence to self or others. If any member of the research team is given such information, he or 
she will make a report to the appropriate authorities.  
A Certificate of Confidentiality (CoC) offers protection against compelled identification of 
research participants by name or other identifying information in any legal proceeding.  
However, information in a medical record is less secure than information in a research record 
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and inadvertent or unwanted disclosure of the contents of a medical record is foreseeable given 
current hospital practices.  Thus, even if a CoC is in place, the level of protection against 
disclosure from the medical record is less.  
Representatives from the Yale Human Investigation Committee may inspect study 
records during internal auditing procedures.  However, these individuals are required to keep all 
information confidential. Authorized representatives of the Food and Drug Administration 
(FDA) may need to review records of individual subjects.  As a result, they may see your name; 
but they are bound by rules of confidentiality not to reveal your identity to others.  
To guard the confidentiality of genetic material, we will do the following:
1)  The genetic testing of your DNA is for research purposes only.  No results of genetic 
testing from this study will appear in your medical record. 
2) Genetic test results will not be made available to you, your doctors, your other 
clinicians or any other clinical staff.  We do not expect the genetic testing done in this study to 
become part of treatment for psychiatric problems or addiction at any time during this study or in 
the next few years to come. If you want to know more about your risks to diseases in which 
genes play a role, we recommend that you speak with a genetic counselor. We will provide you 
with names of genetic counselors in the area if you wish to speak with one. 
3) Information about your genes will be stored in Dr. Joel Gelernter’s laboratory at the 
West Haven VA Medical Center.  These samples will be numerically coded and the key 
connecting the codes to personal identities will be stored in Dr. D’Souza’s laboratory at the 
Connecticut Mental Health Center. Please note that Research on DNA from your blood will be 
conducted primarily in the Laboratory of Psychiatric Genetics, Department of Psychiatry, VA 
Connecticut Health Care System, West Haven Campus, under the supervision of Dr. Gelernter. 
Dr. Gelernter will be responsible for all uses of your genetic-research blood samples and DNA. It 
is possible that DNA from your blood sample will be shared with qualified researchers at the 
VA, Yale or other institutions.  Please note that these DNA samples will have absolutely no link 
to your personal identity. It is possible that Dr. Gelernter will leave VA Connecticut at some time 
in the future. If this occurs, records of genetic information about your DNA will be maintained in 
his new laboratory, with all precautions in place to protect your confidentiality that are described 
elsewhere in this form.
There is a federal law called the Genetic Information Nondiscrimination Act (GINA) 
that, in general, makes it illegal for health insurance companies, group health plans, and most 
employers(except those with fewer than 15 employees) to discriminate against you based on 
your genetic information.  However, it does not protect you against discrimination by companies 
that sell life insurance, disability insurance, or long-term care insurance.
While all efforts are aimed at protecting and guarding your DNA samples, there remains 
the possibility that Yale University could be compelled by a court or a law enforcement agency 
to produce such samples.  In more than sixteen years of collecting DNA samples here at the Yale 
University and VA Connecticut Healthcare System, in which many thousands of samples have 
been collected, no outside agency has ever tried to gain access to any research participant's DNA 
samples.  We believe that the risk of this happening to your sample is small.  The records of 
potential subjects who did not enroll in the study or subjects who withdrew from the study will 
be retained in the same manner as described above.
In Case of Injury
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If you are injured as a result of your participation in this study, treatment will be 
provided.  You or your insurance carrier will be expected to pay the costs of this treatment.  No 
additional financial compensation for injury or lost wages is available. You do not give up your 
legal rights by signing this form.
Voluntary Participation and Withdrawal
Participating in this study is voluntary. You are free to choose not to take part in this study.   
Refusing to participate will involve no penalty or loss of benefits to which you are otherwise 
entitled (such as your health care outside the study, the payment for your health care, and your 
health care benefits).  However, you will not be able to enroll in this research study and will not 
receive study procedures as a study participant if you do not allow use of your information as 
part of this study.
Withdrawing From the Study
If you do become a subject, you are free to stop and withdraw from this study at any time during 
its course. If you choose to withdraw after you have received the study medication we will ask 
you to stay in the clinical unit until it is safe for you to leave. 
To withdraw from the study, you can call a member of the research team at any time and tell 
them that you no longer want to take part.  This will cancel any future appointments.
 
The researchers may withdraw you from participating in the research if necessary.  This might 
happen if you develop serious side effects or if you are not compliant with study procedures. 
Withdrawing from the study will involve no penalty or loss of benefits to which you are 
otherwise entitled.  It will not harm your relationship with your own doctors or with Yale-New 
Haven Hospital and the Connecticut Mental Health Center.
Withdrawing Your Authorization to Use and Disclose Your Health Information
You may withdraw or take away your permission to use and disclose your health information at 
any time. You may withdraw your permission by telling the study staff or by writing to Dr. 
Deepak Cyril D’Souza, Clinical Neuroscience Research Unit, CMHC, 34 Park St., New Haven, 
CT 06519.
If you withdraw your permission, you will not be able to stay in this study.
When you withdraw your permission, no new health information identifying you will be 
gathered after that date.  Information that has already been gathered may still be used and given 
to others until the end of the research study, as necessary to insure the integrity of the study 
and/or study oversight.  
You may also ask that your genetic blood sample be destroyed or that any identifying 
information be permanently removed from the genetic samples.  In this case, your genetic 
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material can only be studied anonymously in the future. This request should be made in writing 
to Dr. Deepak Cyril D’Souza, CMHC Ribicoff Research Center, 34 Park St., New Haven, CT 
06519.
Possible Participation in Future Studies 
We would like to be able to contact you in the future to offer you participation in other 
studies. Giving your permission for the research team to contact you does not obligate you to 
answer any future questions or to participate in any future research – you always have the right 
to decline further participation in research. If you agree to participate in another study, we would 
ask you to read and sign a new consent form. Please initial if you would like to be contacted to 
participate in other studies. 
I agree to be contacted for future research studies: __________________________
Participant’s Initials
Questions
We have used some technical terms in this form.  Please feel free to ask about anything 
you don't understand and to consider this research and the consent form carefully – as long as 
you feel is necessary – before you make a decision.
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Authorization and Permission
I have read (or someone has read to me) this form and have decided to participate in the project 
described above.  Its general purposes, the particulars of my involvement and possible hazards 
and inconveniences have been explained to my satisfaction.  My signature also indicates that I 
have received a copy of this consent form.
By signing this form, I give permission to the researchers to use information about me for the 
purposes described in this form.  By refusing to give permission, I understand that I will not be 
able to be in this research. 
Name of Subject:_____________________________
            
Signature:___________________________________
Date:______________________________________
___________________________________________
___________________
Signature of Person Obtaining Consent
Date
If after you have signed this form you have any questions about your privacy rights, please 
contact the Yale Privacy Officer at 203/432-5919.
If you have further questions about this project or if you have a research-related problem, you 
may contact the Principal Investigator, Dr. Deepak Cyril D’Souza, (203)932-5711 x2594.  If you 
would like to talk with someone other than the researchers to discuss problems, concerns, and 
questions you may have concerning this research, or to discuss your rights as a research subject, 
you may contact the Yale Human Investigation Committee at (203) 785-4688. 
APPROVED BY THE YALE UNIVERSITY IRB 7/12/2018 VALID THROUGH 7/16/2019

Prot_000.pdf: 
NCT01911676 
Translational Neuroscience Optimization of GlyT1 Inhibitor 
 
Project Description 
5/28/2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Translational Neuroscience Optimization of GlyT1 Inhibitor 
Principal Investigator: Deepak Cyril D’Souza, MD 
 
Purpose: Schizophrenia is one of the leading causes of disability, principally because current treatments lack 
substantial efficacy for treating cognitive impairments associated with schizophrenia (CIAS). Deficits in N-
methyl-D-aspartate (NMDA) function are thought to contribute to CIAS by interfering with the integrity of brain 
functional connectivity and neuroplasticity.  Enhancing NMDA receptor function via the glycine site may reduce 
cognitive deficits. Glycine transporter-1 inhibitors (GlyT1Is) act by raising synaptic glycine levels and increasing 
glycine occupancy of the high-affinity (glycineB) coagonist site of NMDA-receptor (NMDA-R) thus enhancing 
NMDA-R function. However, with higher doses of Glyt1Is there is a plateauing and/or worsening of effects 
suggestive of an inverted ‘U’ dose response regulation of NMDA-R function. This study is designed to test the 
efficacy of two doses of active PF-03463275 (40 mg, 60 mg) versus placebo in combination with cognitive 
remediation (CR) for the treatment of CIAS.  
 
Aims:  
• 
Aim #1:To test the efficacy of treatment with  two doses of PF-03463275 (40 mg or 60 mg versus 
placebo) combined with CR to enhance cognitive function in chronic, stable, antipsychotic treated 
patients with schizophrenia as measured by the composite score on the MATRICS Consensus 
Cognitive Battery (MCCB).  
• 
Aim #2: To test the efficacy of treatment of 40mg or 60mg controlled release PF-03463275 BID 
combined with Cognitive Remediation (CR)  in reducing the deficits in LTP observed in schizophrenia. 
 
Background: Schizophrenia is a chronic debilitating illness with a prevalence of approximately 1% in the 
general population worldwide, affecting over 3.0 million individuals in the US. The World Health Organization’s 
Global Burden of Disease 2000 ranked schizophrenia as the fifth leading cause of years lived with a disability. 
Cognitive deficits, for which there are currently no proven treatments, contribute significantly to disability 
associated with schizophrenia. As stated by Thomas Insel, there is an urgent need to develop effective 
treatments for cognitive impairments of schizophrenia (CIAS) (6). The purpose of the current project is to 
employ translational neuroscience approaches to optimally evaluate the efficacy of the glycine transporter-1 
inhibitor (GlyT1I), PF-03463275, that has not been fully tested and to thereby demonstrate its potential for 
efficacy in treating CIAS.  
 
Computerized Cognitive Remediation is associated with improvement in cognitive test performance in 
schizophrenia patients:  We (Johannesen, NCT00923078) have completed testing of 24 chronic schizophrenia 
patients in an in-progress computer-based CR study targeting auditory and visual processing. This 8-week 
study uses a cross-over design with randomization to training of one modality for 4 weeks, and crossing to the 
alternate modality for a second 4 weeks. Figure 6 shows effect-size (Cohen’s d) comparisons across 
MATRICS cognitive tests from baseline to the first 4-week follow-up. Small to medium effect-sizes were 
observed across most cognitive domains in subjects receiving visual training (InSight), exceeding published 
practice effects (5) on MATRICS tests as well as effects of the auditory training (Brain Fitness) condition on all 
measures with the exception of NAB Mazes, BVMT, and WMS-III Spatial Span. These effects were obtained 
using the same visual training software (InSight, Posit Science) and training intensity (5 sessions/week x 4 
weeks) as the trial proposed in the current application, therefore, we are confident that our design will have the 
same efficacy in those receiving CR + placebo and predict enhanced efficacy in the CR + active GlyT1I 
condition. Retention and training compliance have been excellent with 100% follow-up and subjects completing 
96%, on average, of all scheduled InSight training sessions using the incentive payment schedule described in 
this application.   
 
Human visual cortex neuroplasticity (LTP) is a biomarker of NMDA-R dependent neuroplasticity: As reported 
by Cavus et al, 2012, (13) data collected on a small sample of subjects in our laboratory show the expected 
post- stimulation enhancement of N100 ERP amplitude in healthy (aged 51, 34, 27) but not schizophrenia 
(aged 56, 32, 24) subjects (Fig. 7). 
 
Treatment with the combination of Cognitive Remediation and Glycine Site agonist in schizophrenia patients is 
both safe and feasible: In a POC study, we (D’Souza et al) have demonstrated the feasibility and safety of 
combining pharmacotherapy with CR in patients with schizophrenia. Chronic, stable, antipsychotic treated 


patients (n=104) with schizophrenia received the glycine site agonist D-Serine or placebo and CR for 12 weeks 
in a double-blind randomized manner. Both interventions were well tolerated with a ~90 % completion rate 
(62). These results demonstrate our capacity to successfully recruit, engage and retain sufficient patients as 
proposed in this study, and also demonstrate the feasibility of combining pharmacotherapy with CR. 
 
Significance: Schizophrenia has been ranked by the World Health Organization’s Global Burden of Disease 
2000 as the fifth leading cause of years lived with a disability. CIAS affect most patients with schizophrenia 
(52), precede the onset of illness, range from moderate to severe (53), are strongly correlated with functional 
outcome (54, 55) and predict disability and vocational functioning better than positive symptoms (55). While the 
available antipsychotic treatments address the positive symptoms of the disorder, they do not reduce cognitive 
deficits. In fact, there are no approved treatments for the cognitive deficits of schizophrenia. In summary, 
developing effective treatments for the cognitive deficits of schizophrenia will represent a significant step 
forward in the treatment of this major disorder 
 
Inclusion/Exclusion Criteria: 
 
Inclusion Criteria:  
1) Males or females 20 to 65 years of age (inclusive).  
2) DSM-IV schizophrenia or schizoaffective disorder 
3) Ongoing treatment with an antipsychotic except clozapine. 
4) No changes in antipsychotics for at least 3 months.  
5) No psychiatric hospitalizations for the past 3 months.  
6) Genotyped to be CYP2D6 extensive metabolizer genotype.  
7) Able to provide written informed consent. 
 
 
Exclusion Criteria: 
1) Female subjects who are pregnant/ breastfeeding or unwilling to practice established effective 
contraception as determined by the investigator prior to entering the study until 30 days following the 
last dose of the study.  Acceptable contraceptive methods for female subjects include: Double barrier 
contraception or a combination of a barrier contraception and a hormonal implant, injectable, combined 
oral contraceptive, or male partner who has had a vasectomy; IUD or tubal ligation.  
2) Genotyped to be CYP2D6 poor, intermediate, or ultra-rapid metabolizers.  
3) Current or past clinically significant or unstable medical illness (per P.I. discretion) 
4) Current or past history of significant neurological disorder, including head trauma with loss of 
consciousness, history of stroke, Parkinson's disease, epilepsy disorder, conditions that lower seizure 
threshold, seizures of any etiology (including substance or drug withdrawal), those who were taking 
medications to control seizures, or those who had increased risk of seizures.  
5) Evidence or history of significant hepatic disorder, including acute or chronic hepatitis B and acute 
hepatitis C  
6) HIV+ or AIDS.   
7) Any condition possibly affecting drug absorption (e.g. gastrectomy).  
8) Positive urine drug screen for substances of abuse  
9) Treatment with an investigational drug within 30 days or 5 half-lives preceding the first dose of study 
medication.  
10) Clinically significant ECG abnormality (e.g., QTC interval > 450).  
11) Concomitant treatment with medications that interfere with cognitive testing (e.g., benzodiazepine) 
within 12 hours before cognitive testing and cognitive remediation. 
12) Concomitant treatment with drugs or foods that are known to interfere with the function of CYP2D6 
and CYP3A4.  
13) Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >2 times the upper limit 
of normal (ULN) at the screening visit.  
14) Current DSM-IV Axis I diagnosis other than schizophrenia or schizoaffective disorder.  
15) DSM-IV defined psychoactive substance dependence within 6 months of screening or substance 
abuse (excluding nicotine and caffeine) within 3 months prior to screening.  
16) IQ less than or equal to 70, as determined by the Weschler Test of Adult Reading (WTAR) 


17) Treatment with clozapine, lamotrigine or carbamazepine because these drugs may interfere with 
the effect of PF-03463275 on facilitating NMDA-R function. 
18) Treatment with monoamine oxidase inhibitors within 60 days prior to screening. 
19) Treatment of refractory schizophrenia.  
20) Blood donation within eight weeks of the start of the study.  
 
Recruitment: Subjects for both phases of this study will be recruited by advertisements in newspapers and 
websites such as Craigslist and flyers that will be posted at various locations at VACHS, by referral from 
providers and word of mouth. All advertisements and flyers will be reviewed and approved before use by the 
Human Subjects Subcommittee at the VACHS and the Human Investigations Committee at Yale. In the event 
that a subject responds to an advertisement, they will be contacting study staff. Subjects who contact the clinic 
will be invited in for a face-to-face meeting. Furthermore, the research team will reach out to local mental 
health facilities (including the Connecticut Mental Health Center) through “lunch and learns”, etc. for patient 
referrals. A lunch and learn is a meeting that research staff schedule with clinicians and therapists at local 
mental health facilities where an overview of current research protocols are presented and discussed. In the 
event that subjects are referred from clinics or mental health facilities, research staff will require that the 
subjects’ clinician contacts the subject first and then refers the subject to the research clinic. 
 
The investigators and study personnel may work with the mental hygiene clinic to conduct pre-
screening chart reviews to determine potentially eligible subjects for this study. If a patient diagnosed with 
schizophrenia or schizoaffective disorder seems eligible, their primary clinician will be approached for a referral 
for screening. Subjects will not be contacted directly. 
 
Informed Consent: Subjects who may meet entry criteria will be invited to meet with the research staff, who 
will fully explain details, risks and procedures as outlined in the consent form. To ensure understanding of the 
study, the subject will be asked questions about the study procedures and the risks associated with 
participation. This process generally takes about one hour. If it appears that the study subject does not fully 
understand the study, the Principal Investigator (PI) may decide that the subject is not suitable for participation. 
If the subject is still interested after all questions have been answered, he/she will be asked to sign the 
informed consent form. Subjects will be informed that they can decline to participate in the study without 
penalty and will be given the opportunity to withdraw from the study prior to analysis of their data. A copy of the 
consent form will be provided to all subjects.  
 
Great care will be taken to ensure that the subject is able to give informed consent. If any concern arises 
that the study subject did not fully understand the study, the principal investigator may decide that the subject 
is not suitable for participation. This process will involve careful explanation of the consent form by a member 
of the research staff and a post- test to ensure understanding of the procedures and risks of the study. The 
subject will be required to get 75% of all questions and all the asterisked critical questions correct on a consent 
questionnaire in order to participate.  
 
For patients with schizophrenia, family and/or non-research clinicians will be involved in the process when 
available. The patient’s primary clinician i.e. non-research clinician (if applicable) will be required to assent to 
patient’s participation. This is standard procedure for this clinic with all studies that involve patients.  
                                                                                                                                                                                             
Research Design: This is a double-blind, placebo-controlled, within subject POC study of stable patients with 
schizophrenia randomized to either placebo or active PF-03463275 twice daily in addition to their antipsychotic 
(except clozapine) for 2 dosing periods, each lasting approximately 5 weeks. Subjects will begin treatment with 
the study medication upon completion of all baseline procedures. The first week of each treatment will 
represent a lead in period to evaluate the effects of medication alone on LTP and to confirm compliance and 
tolerability. All subjects will receive cognitive remediation in addition to placebo/active PF-03463275 for 
approximately 4 weeks each study period.  
 
Per the P.I.’s discretion, up to 14 days may be added to a treatment period to account for extenuating 
circumstances, such as departmental closures or scheduling conflicts, which would otherwise inhibit 
completion of a period within the intended 5 weeks per study period (see procedures table, Appendix: Table 1). 
For the aforementioned reason, if the subject does not successfully complete a study procedure, he or she 
may be asked to repeat said procedure, a decision that will be made at the discretion of the principal 
investigator.  
 


Screening: Subjects will first undergo a phone screen to initially determine eligibility. Information collected 
during the phone screen will only be used in the event that the subject continues to participate in the study. 
After determining initial eligibility, research staff will provide a brief description of the research and the subject 
will present to the clinic for the screening procedures described below.  
Part I of the screening will consist of consenting and procedures necessary for medical and psychiatric 
clearance (i.e., SCID, labs, EKG, physical). Part II of the screening process will consist of history verification, 
and testing (i.e., assessments of intelligence and cognition). However, the procedures may need to be divided 
differently between screening visits in cases where subjects have limited time to dedicate to the screening 
appointments.  Screening procedures take approximately 8 hours, and may require multiple visits. Once all 
screening procedures have been collected, research staff as well as the principal investigator will review all 
relevant information and determine, based on the inclusion and exclusion criteria, if the subject will continue 
with the remaining study procedures. For those found ineligible, the information collected during the phone 
screen will be kept, with the permission of the subject.  
 
At the screening session, the following procedures will take place: 
1. The subject will receive a full, written explanation of study procedures and sign a consent form. The 
subject will be required to successfully complete a questionnaire that will help us confirm their 
understanding the risks of this study before participation. They will be given two attempts and they will 
be required to answer all questions correctly. Any questions will be answered and a physician or nurse 
will be available to answer any medical questions. 
2. Subjects will receive a detailed evaluation including a medical history and a physical examination. 
3. A psychiatric evaluation and a Structured Clinical Interview (SCID) for DSM-IV (non-0patient) for 
healthy controls will be conducted. 
4. Laboratory tests will include urine toxicology and EKG. 
5. A 10-mL blood sample will collected at screening for CYP2D6 genotyping into an appropriately labeled 
plastic EDTA tube. The whole blood will be transported to Joel Gelernter’s laboratory for standard 
CYP2D6 analysis. 
 
6. Intelligence will be measured using the Wechsler Adult Intelligence Scale IV (WAIS-IV)  and will be 
added as a covariate in the neuropsychological data analysis. 
7. Handedness will be confirmed via the Edinburgh Handedness Scale  
8. Subjects will meet with a study doctor for cognitive assessments.   
9. Subjects will be asked to identify a collateral source of information at the beginning of the screening 
process (explicitly stated in the consent form) and sign a release of information providing us permission 
to contact the collateral.  A family member, significant other, spouse is preferred.  We then contact the 
collateral to elicit any information that might disqualify the subject or suggest risk to the subject. In 
instances where there are discrepancies between the information provided by the subject and that by 
the collateral, we usually disqualify subjects. 
10. Subjects will be asked to refrain from all illicit drugs, alcohol, caffeine and other medications for 1 week 
prior to the test days. 
 
Randomization to PF-03463275: Subjects will be randomized to one of two doses of the glycine transporter 
inhibitor (GlyT1I) PF-03463275 (40 mg or 60 mg) and placebo twice daily in addition to their standing 
antipsychotic dose for two treatment periods each lasting approximately 5 weeks. Treatment periods will be 
separated by a washout period lasting approximately 3 weeks. Randomization will be stratified by antipsychotic 
treatment and screening performance Intelligence Quotient (WTAR estimated  FSIQ  71-90 and >91).  Other 
variables of interest e.g., cognitive test performance (MCCB composite score), BDNF genotype, BDNF levels 
(low, medium and high), antipsychotic dose, that cannot be stratified because of sample size limitations will be 
examined post-hoc. The dose of PF-03463275 has been determined based upon sub-study 1: doses that 
produced at least 10% occupancy and attenuation of Ketamine effects on fMRI response to a spatial working 
memory task will be used in Sub-Study 2. 
 
MCCB: The MCCB (5) consists of 10 tests and provides standard scores and percentiles for each of seven 
cognitive domains. Domains assessed include: speed of processing, attention/vigilance, working memory 
(verbal and visual), verbal learning, visual learning, reasoning and problem solving, and social cognition. The 
MCCB was developed by an expert panel of researchers, under NIMH contract, as a broad yet sensitive 


measure to assess cognitive change in treatment studies. The battery includes alternate test forms for 
repeated administrations. The MCCB will be administered at baseline and follow-ups. Change on the MCCB 
composite score will be calculated to assess for the overall effect of treatment, with change in specific cognitive 
domains including verbal and visual learning and short-term/working memory examined as exploratory 
analyses.   
 
Visual LPT Paradigm: A visual LTP procedure (13, 74) will be administered as a probe of visual cortical 
neuroplasticity. In brief this paradigm consists of six experimental blocks, each of 2 min duration (Figure 12), 
administered during electroencephalographic (EEG) recording. The first two blocks serve as baselines, during 
which subjects complete a visual target detection task. A central fixation cross is replaced by one of two stimuli 
(Figure 11, panel A) at pseudorandom order with duration of 33ms and average stimulus-onset asynchrony 
(SOA) of 1216ms (jittered 1075-1340ms); a circular checkerboard (10.5 x 10.5cm, subtending 6o of visual 
angle) or blue square checkerboard (17.5 x 17.5cm, subtending 10o of visual angle) against a white 
background. Each block consists of 100 trials, with the circular checkerboard presented 90% (standard) and 
the blue square checkerboard 10% (target). Subjects are instructed to keep their dominant index finger on a 
response key button and to respond as quickly as possible to the blue square checkerboard. This target 
detection task is used to maintain alertness to the visual stimuli and target trials are not included in analysis of 
LTP. Baseline blocks are followed by a 2-minute period of visual high-frequency stimulation (HFS), in which the 
circular checkerboard is presented alone at a rate of 8.87Hz (113ms mean stimulus onset asynchrony; 1000 
presentations). Subjects are instructed to fix their gaze on the centrally presented “flickering” stimuli and to 
relax while remaining as still as possible. This rate of high-frequency stimulation is designed to induce 
potentiation, analogous to the tetanizing stimuli in classic LTP procedures, and produces a prominent ~9Hz 
visual steady state response over posterior-occipital electrode sites. Subjects are instructed to close their eyes 
for a 2-minute rest period following high-frequency stimulation to allow visual after-effects to disappear. The 
rest period is followed by three post-test blocks, identical to the baseline blocks, beginning 2-, 4-, and 18-
minutes following stimulation. LTP is characterized by an increase in visual N100 ERP amplitudes evoked by 
the circular checkerboard stimuli from baseline to post-test blocks. 
 
Risks and Benefits:  
1. Screening: Healthy control subjects (HCS) and schizophrenic subjects (SZS) will undergo a Structured 
Clinical Interview for DSM-IV conducted by a research assistant and a psychiatric evaluation by the 
research psychiatrist at the VA Hospital in West Haven. The diagnostic interviews may cover issues, 
which are stressful to a person, for example, questions regarding the experience of paranoid thoughts 
or social isolation. Thus, SZS may experience some distress of worsening of psychiatric symptoms. 
2. Loss of Confidentiality: Participation in research may involve a loss of privacy and confidentiality. 
Therefore, extensive measures are in place to protect the confidentiality of subjects. 
3. Treatment with PF-03463275: In clinical trials in healthy controls and patients with schizophrenia, 
common risks reported include fatigue, thirst, somnolence, insomnia, headache, akathisia, tremors, 
nausea, increased urination, gastrointestinal disturbances including abdominal pain, nausea, 
constipation and diarrhea. Visual disturbances include the brightening of vision and perception of 
flashing lights and one patient with schizophrenia also reported blurring of vision. These were transient 
and not associated with any visual changes on further testing. Palpitations, tachycardia and 
hypotension (in one subject) were noted, but resolved without any medical intervention. One patient 
with schizophrenia had ventricular systoles and was noted to have a 20 msec increase in QTc interval. 
Finally, 2 subjects with schizophrenia had elevations in AST/ALT levels and one subject had elevated 
glucose level attributable to treatment with PF-03463275. Thorough screening and frequent 
assessments for adverse events (See Section XII) are in place to mitigate the risks. Certain foods and 
medications may interfere with the metabolism of PF-03463275 and result in very low or high drug 
levels. This may result in loss of efficacy or increased risk of adverse events. Subjects will be advised 
to avoid these medications and this will be confirmed at each study visit. These include: Drugs or 
foods/food products that inhibit CYP2D6 and CYP3A4 (e.g., quinidine, fluoxetine, paroxetine, 
amiodarone, cimetidine, clarithromycin, diltiazem, erythromycin, fluvoxamine, nefazodone, nelfinavir, 
ritonavir, troleandomycin, and verapamil, indinavir, itraconazole, ketoconazole, mibefradil, grapefruit 
and grapefruit juice). Drugs that induce CYP3A4 will also be excluded (for e.g., carbamazepine, 
phenytoin, phenobarbital, rifampin and rifabutin).  


4. Long Term Potentiation - Event Related Potentials: There are minimal risks associated with 
EEG/ERP recording. Traditionally, scalp abrasion has been used to improve signal impedance at the 
electrode site. The EEG/ERP system used in this laboratory is a high-impedance system and does not 
require scalp abrasion to obtain clean recording. A conductive gel is applied, which can be easily 
washed out of the subject’s hair with warm water. A shower facility for hair washing and sterile linens 
are available in the laboratory. Electrode caps and sensors will be washed and sterilized between 
subjects to minimize the risk of transmitting infection. 
5. Cognitive Remediation: There are no known physical risks associated with computer-based cognitive 
remediation. Fatigue and frustration during training are possible. If this occurs, subjects will be 
encouraged to take breaks, during which they can drink coffee or halt training for the day. Research 
staff will monitor subjects during training and may advise them to seek further treatment if symptoms 
worsen as a result of participation in the study. 
a. Reduction of Risk: Subjects will be encouraged to maintain the pace of cognitive exercises and 
not to be worried about performance. They will be encouraged and reassured. If they need a 
break, they will be encouraged to take one and return. The cognitive remediation in this study 
allows for a flexible training schedule. If subjects appear to be getting distressed, they will have 
the opportunity to talk with one of the investigators and may even be asked to return for the 
session. At the Learning Based recovery center, Dr. Bell has enormous experience using 
cognitive remediation in patients with schizophrenia. Overall, this is tolerated very well and 
subjects usually find it very motivating and helpful. Some of the behavioral questions may be 
distressing to patients. This risk is discussed in the consent process and subjects will be 
reminded that they can stop at any time and can choose not to answer. In case of marked 
worsening of symptoms, they will be evaluated by a psychiatrist, referred to their usual 
outpatient treater. Further, if indicated they may be escorted to the ER for an evaluation or 
admission as clinically indicated. 
 
SAFETY 
 
Data and Safety Monitoring Plan: The safety data is reviewed after every test day, during weekly research 
team meetings, and will be suspended or modified if indicated.   
Adverse events will be graded in severity as follows: 
0 
No adverse event or within normal limits 
1 
Mild adverse event 
2 
Moderate adverse event 
3 
Severe adverse event resulting in hospitalization or prolongation of existing hospitalization, a 
persistent or significant disability/incapacity, or a congenital anomaly/birth defect. 
4 
Life-threatening or disabling adverse event 
5 
Fatal adverse event 
The expected effects of Ketamine will not be recorded as adverse events. 
Adverse events > level 3 will be reported to the IRB within 24 hours. Other adverse events will be reported to 
the IRB in a timely manner, using the following predefined causal relationships: 
i. 
Definite: Adverse event(s) will clearly be related to investigational agent(s) or other intervention 
ii. 
Probable: Adverse event(s) will likely be related to investigational agent(s) 
iii. 
Possible: Adverse event(s) may be related to investigational agent(s) 
iv. 
Unlikely: Adverse event(s) will doubtfully be related to investigational agent(s) 
v.  
Unrelated: Adverse event(s) will clearly not be related to the investigational agents(s) 
Serious, unanticipated and related adverse events will be reported to VA-HSS and Yale HIC. 
 
Informed Consent: Subjects who meet entry criteria mentioned above will be invited to meet with the research 
staff, who will fully explain risks and procedures as outlined in the consent form.  After reviewing this 
information and answering questions, informed consent will be obtained from all subjects. The informed 
consent form (see attached), which will be given to the participating subjects, explains all the information 
pertaining to this study such as the objectives of the study, the procedures, risks and benefits, confidentiality, 
safety measurements, payment and other aspects of the study.  Understanding of the information prior to 
obtaining consent is verified using a questionnaire (see attached). 
 


Economic Considerations: Sub-study 2: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subjects will be compensated up to $50 for completion of screening processes, which will take place at 
the VACHS and Yale University. These aforesaid processes will take approximately 8 hours and may take 
multiple visits. In this case, the total amount of the screening will be split between the visits.  For example, the 
subject will be paid $25 for the first visit and $25 at the subsequent screening.   
 
Subjects can earn up to $1, 555 for completion of all study procedures. Participants will receive 
compensation only for study visits that are attended. Payments for screening, baseline and week 1 will be 
made via cash. All other visits will be paid via debit card unless otherwise requested by the subject or his/her 
conservator, and agreed upon by the P.I.  
 
To encourage participation in cognitive training, additional incentive payments will be dispensed for 
cognitive training activity, amounting up to $440. Training will be administered over approximately 8 weeks, 
during which you will be asked to complete approximately 5 sessions per week, for a total of about 40 sessions. 
Incentive payments will be earned in blocks of 5 sessions, and dispensed according to the schedule outlined in 
the Economic Considerations Table. A maximum of 5 sessions can be completed each week, and no additional 
incentive payments will be made after 40 training sessions. A partial payment may be made at the final training 
session based on the percentage of training you complete toward the next payment point.  
 
 
In addition to the compensation for each in-person visit, subjects will be compensated $5 for completing 
each compliance monitoring or CAROMA visit by phone. CAROMA visits will only be completed on weekdays 
that the research clinic is open. Subjects may earn up to $350 dollars for completing all possible CAROMA 
visits. 
   
 
 
Sub-study 2Visit 
Amount 
Method 
Screening Visit 1 
$25 
Cash 
Screening Visit 2 
$25 
Cash 
Baseline 
$75 
Cash 
Period 1 
Week 1 
$75 
Cash 
Week 2 
$100 
Debit Card 
Cog Rem-Session 5 
$20 
Debit Card 
Week 3 
$100 
Debit Card 
Cog Rem- Session 10 
$30 
Debit Card 
Week 4 
$100 
Debit Card 
Cog Rem- Session 15 
$40 
Debit Card 
Week 5 
$100 
Debit Card 
Cog Rem- Session 20 
$50 
Debit Card 
Washout Week 1 
$20 
Debit Card 
Washout Week 2 
$20 
Debit Card 
Period 2 
Week 9 
$100 
Debit Card 
Cog Rem- Session 25 
$60 
Debit Card 
Week 10 
$100 
Debit Card 
Cog Rem- Session 30 
$70 
Debit Card 
Week 11 
$100 
Debit Card 
Cog Rem- Session 35 
$80 
Debit Card 
Week 12 
$100 
Debit Card 
Cog Rem- Session 40 
$90 
Debit Card 
Follow- Up 
$75 
Debit Card 


 
 
REFERENCES 
 
1. 
Bergeron R, Meyer TM, Coyle JT, Greene RW (1998): Modulation of N-methyl-D-aspartate receptor 
 
function by glycine transport. Proceedings of the National Academy of Sciences of the United States of 
 
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Chen L, Muhlhauser M, Yang CR (2003): Glycine tranporter-1 blockade potentiates NMDA-mediated 
 
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3. 
Supplisson S, Bergman C (1997): Control of NMDA receptor activation by a glycine transporter co-
 
expressed in Xenopus oocytes. Journal of Neuroscience. 17:4580-4590. 
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Javitt DC (2012): Glycine transport inhibitors in the treatment of schizophrenia. Handb Exp 
 
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Nuechterlein KH, Green MF, Kern RS, Baade LE, Barch DM, Cohen JD, et al. (2008): The MATRICS 
 
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Insel T (2012): Experimental Medicine. 
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TABLE 1:Substudy 2 Procedures 
 
Screen 
 
Baseline 
(2 weeks) 
Period 1 
(5 weeks) 
Washout 
(3 weeks) 
Period 2 
(5 Weeks) 
 
Follow -
Up 
 
Week 
Screen 
-2 
-1 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Day 
-14 
-7 
0 
7 
14 
21 
28 
35 
42 
49 
56 
63 
70 
77 
84 
91 
98 
SCID 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
WTAR 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Psych  
Evaluation 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Genotyping 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomizat
ion 
 
 
 
x 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
PF v 
Placebo  
 
 
 
x 
x 
x 
x 
x 
x 
 
 
x 
x 
x 
x 
x 
x 
 
CR 
 
 
 
 
x 
x 
x 
x 
x 
 
 
 
x 
x 
x 
x 
x 
 
PANSS 
 
 
 
x 
 
x 
 
x 
 
 
 
x 
 
x 
 
x 
 
 
SGI 
 
 
 
x 
 
x 
 
x 
x 
 
 
x 
 
x 
 
x 
x 
 
PAOFI 
 
 
 
x 
 
x 
 
x 
x 
 
 
x 
 
x 
 
x 
x 
 
Movement 
Exam 
 
 
 
x 
 
x 
 
x 
 
 
 
x 
 
x 
 
x 
 
 
MCCB 
 
x 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
x 
LTP 
 
 
 
x 
 
 
 
 
x 
 
 
x 
 
 
 
 
x 
 
PK 
 
 
 
x 
x 
x 
x 
x 
x 
 
 
x 
x 
x 
x 
x 
x 
 
BDNF 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC 
x 
 
 
x 
 
x 
 
x 
 
 
 
x 
 
x 
 
x 
 
 
CMP 
x 
 
 
x 
 
x 
 
x 
 
 
 
x 
 
x 
 
x 
 
 
ECG 
x 
 
 
x 
 
x 
 
x 
 
 
 
x 
 
x 
 
x 
 
 
Utox 
x 
x 
x 
x 
 
x 
 
x 
 
x 
x 
x 
 
x 
 
x 
 
 
SCID: Structured Clinical Interview for DSM IV; WTAR: Wechsler Test of Adult Reading; CBC: Complete Blood Count; CMP: Comprehensive 
Metabolic Panel; ECG: Electrocardiogram; Utox: Urine Toxicology screen; CR: Cognitive Remediation; PANSS: Positive and Negative 
Syndrome Scale; SGI: Sensory Gating Inventory; PAOFI: Patient Assessment of Own Functioning Inventory; LTP: Long Term Potentiation; 
BDNF: Brain Derived Neurotrophic Factor.  Per P.I. discretion, study procedures may be repeated, and the duration of participation may be 
extended to account for scheduling conflicts and extenuating circumstances. Thus, the number of weeks listed per period may vary. 


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SAP_001.pdf: 
NCT01911676 
Translational Neuroscience Optimization of GlyT1 Inhibitor 
 
Statistical Analysis Plan  
5/28/2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan: 
 
All dependent measures were assessed for normality using normal probability plots. 
Descriptive statistics were calculated prior to analyses. Each dependent variable was analyzed 
using a mixed effects model with dose (placebo, low, high), visit (pre- vs. post-drug), their 
interaction and period (first or second) as main effect. Interactions involving period were also 
assessed but were dropped from the models for parsimony. Subject was the clustering factor 
and the best-fitting variance-covariance structure for the repeated measures in each model was 
selected based on Schwartz’ Bayesian Criterion. Least square means and standard errors were 
calculated to describe the patterns of means for each outcome. Post-hoc mean comparisons 
were tested to explain significant effects in the models. Additionally, for each outcome effect 
slices for the interaction are reported although those should be interpreted with caution when 
there are no significant interactions.