Clinical trial NCT03321617
Conditions: Clinical High Risk for Psychosis
Sponsor: New York State Psychiatric Institute
Start date: 2018-04-17; Completion date: 2020-03-13
Enrollment: 16 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Participants will be administered several doses of pomaglumetad (POMA) (low and high doses) over 14 days to individuals at clinical high risk for developing psychosis and use magnetic resonance imaging (MRI) brain imaging to determine whether these doses of POMA are affecting glutamate levels.

Detailed description:
A double-blind, randomized, phase 1b, multiple dose trial of 14 days of treatment with POMA (80 mg, 160 mg, 240 mg, 320 mg) in clinical high risk patients to determine which dose, if any, reduces glutamate and metabolism using MRI techniques. The GO NO-GO decision will be whether or not any dose tested in the R61 phase of the trial decreases left hippocampal CA1 region cerebral blood volume (CBV).

Arms: arm 1: Subject will take 40mg pomaglumetad methionil (POMA) twice a day for 14 days. arm 2: Subject will take 80 mg pomaglumetad methionil (POMA) twice a day for 14 days arm 3: Subject will take 120 mg pomaglumetad methionil (POMA) twice a day for 14 days arm 4: Subject will take 160 mg pomaglumetad methionil (POMA) twice a day for 14 days
Interventions: intervention 1: Pomaglumetad methionil
Intervention descriptions: intervention 1: metabotropic glutamate 2/3 receptor (mGlu2/3R) agonist

Protocol documents:
ICF_002.pdf: 
For emergency or questions call:                                           
  
Dr. Ragy Girgis at 646-775-5553                                          
   
 
1 
V. 8/20 
Consent Cover Sheet 
Glutamate reducing interventions in schizophrenia 
 
Below is a summary of the study you are being asked to participate in. This outline is meant 
as a guide for you to use while considering the study and reading the consent form. It is not 
meant to replace the consent form which you will need to sign if you decide to participate in 
the study. The consent form contains detailed information about the study and the risks you 
will need to consider in making your decision.  
 
Overview:  
• This study has not been designed for your benefit.  
• You are being asked to participate in a research study that is designed to evaluate the 
effect of a drug called LY2140023 (Pomaglumetad or “POMA” for short) on a naturally 
occurring chemical called glutamate in the brain. You will be randomly assigned to take one 
of four doses of POMA twice a day for 14 days by mouth. 
• You will have two magnetic resonance imaging (MRI) brain scans during which you will 
receive an injection of gadolinium as a contrast agent, each scan takes about one hour to 
complete. One scan is done before starting the study drug and one at the end of the study 
drug. You will also take some pen and paper tests and an interview to see how you are 
feeling and thinking.  
Some of your visits may be conducted remotely using the telephone or HIPAA-compliant 
video teleconferencing. 
There are risks associated with participating in this study. These are discussed in detail in 
the consent form. 
 
Risks: 
• POMA is an experimental drug being developed by Denovo, for treatment of psychiatric 
illnesses, including psychosis. The most common side effects of POMA are inability to 
sleep, an increase in one type of white blood cells (eosinophils), feeling anxious, feeling 
sick to your stomach (nauseous), feeling restless or upset, an infection of the upper 
breathing system, vomiting, rashes, headaches, dizziness, increases in muscle enzymes in 
the blood, high blood pressure, stomach pain, constipation, and feeling sleepy. Seizures are 
a rare but possible risk. Doses as high or higher than the highest dose that you could receive 
in this study (160 mg twice a day) has been taken by 24 healthy people without psychiatric 
illness for 11 days in a previous study without significant side effects. No one has ever taken 
POMA at these higher doses for as long as you may be taking them. Please see the Risks 
section of the consent form for detail regarding rare side effects. 
• The contrast agent used in the MRI, gadolinium, may have side effects, including nausea 
and a skin reaction. People with kidney disease should not receive gadolinium. The details 
of the common and rare side effects are listed in the consent form and you can discuss these 
with the study doctor. 
• You are not expected to notice any improvement in your thinking or symptoms during this 
study. Even if you do, this is not expected to last after you finish the study.  
• You don’t need to participate in this study to receive help for your symptoms. There may 
be treatments available to help you, and your doctor can discuss these options.  
• Like all research, your decision is up to you – taking part is voluntary. Also, you cannot 
participate if you have kidney disease. 


For emergency or questions call:                                           
  
Dr. Ragy Girgis at 646-775-5553                                          
   
 
2 
V. 8/20 
 
Glutamate reducing interventions in schizophrenia  
Patient Consent Form 
 
Overview/Study Purpose 
 
We are asking you to take part in a research study.  You are being asked to participate 
because you show one or more symptoms that sometimes lead to developing psychosis.  
This does not mean that you will develop psychosis.  Other people who show these 
symptoms do not always develop psychosis.  All participants in this study will receive one 
of four different doses of POMA.  In addition, some participants may not receive active 
medication during the course of the research.   To join the study is voluntary. 
 
This study is funded by the National Institute of Mental Health (NIMH).  In this study we 
will be testing a drug to see if its helps treat brain problems that we think happen in people 
who have a chance that they will develop a disorder such as schizophrenia.  The purpose 
of the study is to learn about the effects of the drug LY2140023’s (Pomaglumetad or 
“POMA” for short) effects on brain function.  Researchers think that treating a brain 
region (the hippocampus) with POMA may reduce the risk of developing schizophrenia. 
POMA is an experimental medication being developed by a company called Denovo for 
conditions such as psychosis. Its use in this study is experimental. As part of this study, 
you may be exposed to a high dose of POMA for two weeks. Only a small number of 
other people have taken doses in this higher range in previous studies. No people have 
previously taken such doses for as long as 2 weeks.  It is important that you understand 
that this study was not designed for your benefit. By participating, you will help 
researchers answer the goals of the study. There are risks associated with participation; 
these are described in the Study Risks section.  Dr. Scott Small is the principal 
investigator and the person in charge of the study at New York State Psychiatric Institute 
(NYSPI). Study procedures will be conducted at NYSPI as well as the Neurological 
Institute of New York at Columbia University. The study will enroll 50 people at 
Columbia University and NYSPI. 
 


For emergency or questions call:                                           
  
Dr. Ragy Girgis at 646-775-5553                                          
   
 
3 
V. 8/20 
 
Voluntary participation 
Participation in this project is voluntary, and you may refuse to participate or discontinue 
participation at any time without loss of benefits to which you are otherwise entitled.  A 
decision not to participate in this study, or to withdraw at any time, will not affect your 
present or future medical care or employment at either the Columbia University Medical 
Center or the NYS Psychiatric Institute or COPE.  On the other hand, we might terminate the 
study without regard to your consent under circumstances where continuing the study would 
not be safe, such as a pregnancy, or a worsening of your symptoms, or a severe medical 
problem, such as seizures.  We will disclose to you during the study any significant findings 
from the research that may affect your willingness to continue participation.    
 
Also, please note that there would be added risk if you were to participate in a trial in 
addition to this trial at the same time. If you are planning to participate in another trial at the 
same time as this one, you will not be allowed to participate in this trial. 
 
Alternative Treatments/Alternatives to participation The information being collected is 
for research purposes only and is to learn more about brain function and psychosis risk, not 
about you.  It is not necessary to participate in this research study to have an MRI, and the 
MRI done as part of this study is not the same as one done for medical purposes.  The goal is 
not to provide treatment to you. There are treatments that may help improve symptoms you 
may have that are common in patients in the COPE or Lieber clinics, including treatments 
that do not involve taking medication. Your doctor can discuss these options with you at any 
point, whether you decide to participate in this study or not. 
 
Study Procedures 
 
General Information: 
 
This study will last about 4 weeks. During the study, there will be up to 5 visits to the clinic for 
study procedures as detailed below.  There is a screening period that lasts up to 14 days with tests 
and procedures to find out if you are eligible to be in the study. During screening, the study doctor 


For emergency or questions call:                                           
  
Dr. Ragy Girgis at 646-775-5553                                          
   
 
4 
V. 8/20 
will ask you about symptoms you may have that might indicate an increased risk for psychosis. 
You will have a physical exam and blood and urine tests, as well as an EKG to measure the 
electrical activity of your heart.  A small portion of the blood drawn will be used for DNA analysis 
to see how your genetic makeup may affect how POMA affects you. You will be asked not to eat 
after midnight the day before this visit so that fasting blood tests can be done in the morning. About 
2 tablespoons of blood will be taken for standard tests. Urine will be tested for drugs. If you are a 
woman, you will have a blood pregnancy test. If you are eligible when screening is complete then 
you will enter a 2-week treatment phase. You will be randomly assigned (by chance, like the flip of 
a coin) to receive one of four doses of POMA. Neither you nor the study doctor will know which 
dose of POMA you are taking, but they can find out in an emergency. 
 
Outline of Procedures: 
• You will always take study medication 2 times a day: morning and at bedtime. Your study 
doctor will monitor you for side effects on study visits. In addition, research staff will 
observe take each of your doses via hipaa compliant video. 
• During the study you will be asked about your psychiatric symptoms and have tests of your 
cognitive function (such as memory and concentration). At every visit, you will also be reminded to 
take your study drug first thing in the morning and at bedtime.  If you forget to take a dose of study 
medication, --simply skip that dose, and take the next scheduled dose.  The study drug will be given 
to you during your study visits. You will be reminded to bring back all bottles of study drug every 
visit even if you took all study drug. On days 7 and 14 after starting the investigational drug, we will 
evaluate how you are feeling on the study drug and whether you have any side effects. We will take 
blood and urine samples, ask questions about your symptoms, and test your cognition (like your 
attention and memory). We will also draw blood samples to look at blood levels of POMA on days 7 
and 14. These visits will take 2-3 hours. 
• MRI (Magnetic Resonance Imaging). You will receive an MRI before you begin taking POMA, 
and on Day 14 of being on POMA. The MRI uses strong magnetic fields and radio waves to take 
pictures of your brain. The MRI scanner to be used in this study works with a 3T magnet. This 
magnet is stronger than the magnets used routinely in scans done for clinical purposes. MRI 
involves lying on a table that slides into a large magnet shaped like a cylinder. Before beginning the 
imaging procedure, we will make sure that you do not have a pacemaker or any metallic implants 
(other than tooth fillings, or braces), and you will be asked to remove any metal or magnetized 


For emergency or questions call:                                           
  
Dr. Ragy Girgis at 646-775-5553                                          
   
 
5 
V. 8/20 
objects (such as keys, chins, hairpins, or credit cards). You will be asked to lie flat on your back in 
the MRI scanner for 45-60 minutes. You will be asked to remain as still as possible. You will not 
feel anything, but will hear a knocking noise. This is a normal sound produced by the MRI scanner 
and does not indicate that anything is wrong. On the day of the scan, you will be asked to take some 
pen and paper tests and to answer some questions about how you are thinking and feeling.  This 
testing will take a total of 2.5 hours. You will receive a contrast agent gadolinium.   Gadolinium is 
given to you by an I.V.  An I.V. uses a small needle to place a small plastic tube into your vein.  
The small tube is connected to a source of water and the contrast solution, and during the MRI scan, 
the contrast and water are pushed into your vein.  Most people do not notice the injection part of the 
study, but a cool sensation in your arm is a common and normal response to have.  If at any time 
during the injection of the contrast agent you feel uncomfortable or are sick to your stomach, you 
can notify the imaging staff immediately by pressing a button that they give you at the beginning of 
the scan. Nausea may occur due to the POMA, or the gadolinium, and vomiting in the scanner could 
be dangerous. Therefore, it is important to alert staff immediately if you feel nauseated or like you 
need to vomit so you can be removed from the scanner. The scan will then be stopped and the study 
doctor will evaluate you. 
• Study participants who withdraw from the study early for any reason are eligible to receive payment 
for procedures completed to the time of study withdrawal. 
• Upon study completion, you will not know what dose of POMA you received. POMA will not be 
available to you even if it helped because it is an experimental medication. 
• To participate in the study, you must be willing to come to all study visits and to follow all study 
procedures and instructions. 
• Some of your visits may be conducted remotely using the telephone or HIPAA-compliant video 
teleconferencing. 
 
End of Study Clinical Treatment 
You will be eligible for treatment in NYSPI’s outpatient clinic (COPE clinic) for two years as 
part of COPE or you may continue with your current treatment provider. The treatment in 
NYSPI is free except for the cost of medications. 
 
Early Termination of the Study 


For emergency or questions call:                                           
  
Dr. Ragy Girgis at 646-775-5553                                          
   
 
6 
V. 8/20 
At any point during this study you may decide to stop participating. The study doctor (Dr. Girgis) 
may also decide to stop your participation in the study if your condition worsens or if you develop 
side effects or complications. At that time we will ask you to complete some end of study tests. 
Completing that final testing is also voluntary.  Even if you do not finish taking part in this research 
study, you will be eligible to receive clinical treatment, as described in the section “End of Study 
Clinical Treatment.” 
 
Standby 
Additionally, you may be asked to come in as a standby subject. If you agree to be a standby 
subject, you will be asked to come in on a day when a brain scan is scheduled for another participant. 
If for some reason the original participant does not complete the imaging procedures, you will be asked 
to participate in the imaging procedures in place of that person. If the original participant does 
complete the imaging procedures, you will be paid for your time and sent home. We expect that you 
will have to wait between 1-3 hours as a standby participant. You can choose to be a standby subject 
by checking one of the boxes found at the end of this consent form. Please be aware that you may be 
asked to be a standby subject multiple times. We estimate that you may be asked to be a standby 1-3 
times before you are scheduled for your own imaging scan. 
 
Study Risks 
Risks and Discomforts Associated with POMA 
As further described in this section, the most serious side effects associated with POMA and similar 
medications in previous trials have been seizures and rashes. Nausea is also experienced by people 
who take POMA. In clinical studies to date, POMA has been given to 582 healthy people and 
approximately 2,877 patients with schizophrenia or schizoaffective disorder. Most of these people 
received doses in the lower range of what is possible in the present study. Doses of POMA as high or 
higher than the highest dose that you could receive in this study (160 mg twice a day) have been taken 
by 24 healthy people without psychiatric illness for 10 days in a previous study without significant 
side effects. 44 patients with schizophrenia completed a multiple dose escalation study over a dose 
range of 160 to 480 mg BID for 7 days. Therefore, you might get a dose that relatively few people 
have been exposed to so far. No one has ever taken POMA at these higher doses for as long as you 
may be taking them. 
 
In less than 1% of patients with schizophrenia who were treated with POMA, events of sudden, 
uncontrollable, and rapid shaking or seizures have been reported. These periods of rapid and 
uncontrollable shaking or seizures appear to have been associated with POMA. Your doctor may ask 
you additional questions to make sure you are not at risk for this event. Because of these experiences, 
events of sudden, uncontrollable, and rapid shaking or seizures will be monitored. Be sure to tell your 
study doctor immediately if you experience sudden, uncontrollable, and rapid shaking or seizures. 
There have also been reports of muscle spasms and skin rashes.  


For emergency or questions call:                                           
  
Dr. Ragy Girgis at 646-775-5553                                          
   
 
7 
V. 8/20 
 
The most common adverse events (10% or more) in studies conducted in healthy people were: nausea, 
headache, vomiting, and dizziness. The following serious adverse events have been reported in healthy 
subjects (1 person each): infected sebaceous cyst (skin infection), deep vein thrombosis (clot in vein), 
pulmonary embolism, and syncope due to vasovagal event (Fainting). You should let the study doctor know 
immediately if you become nauseous during the MRI scan.  
 
Risks and Discomforts in 1555 Patients with Schizophrenia Taking POMA 
Frequency 
Risks and Discomforts 
Common 
At least 1% to 
9.9% 
• 
Inability to sleep 
• 
Increase in one type of white blood cells (called eosinophils) 
• 
Worsening of schizophrenia 
• 
Feeling anxious or apprehensive 
• 
Headache 
• 
Feeling sick to the stomach (nausea) 
• 
Feeling restless and upset 
• 
Vomiting 
• 
Skin reactions or rashes 
• 
Increase of muscle enzymes in the blood 
• 
High blood pressure 
• 
Stomach pain 
• 
Constipation 
• 
Feeling sleepy 
• 
Indigestion 
• 
Weight loss 
• 
Shakiness or trembling, muscle movements without purpose 
• 
Bronchitis 
• 
Feeling sad, hopeless, worthless, or pessimistic 
• 
An unpleasant or uncomfortable emotion such as sadness, feeling restless 
and upset, and feeling irritable. 
• 
Fast heart rate 
• 
Weakness or loss of strength 
• 
Restlessness or inability to sit still 
• 
Soft or watery stools 
• 
Muscle and joint stiffness 
• 
Muscle stiffness and shaking 
• 
Abnormal sleep patterns 
• 
Toothache 
• 
Dizziness 
 
Some patients died during prior trials from suicide, some on active medication and some on placebo. 
So, we do not know if the POMA medication increases risk of suicide. But if you begin to have 
thoughts of suicide or are feeling more down or worse in other ways, you should alert study staff 
immediately 
 
 


For emergency or questions call:                                           
  
Dr. Ragy Girgis at 646-775-5553                                          
   
 
8 
V. 8/20 
An increased level of POMA in blood has been observed in subjects who have problems with their 
kidneys compared with subjects who have normal kidney function. No problems appeared to be 
associated with the increased levels of drug in the blood, after a single dose; however, multiple doses 
have not been administered in subjects with kidney problems and it is not known whether there will 
be problems associated with this increased exposure. 
 
If you are taking an antidepressant that works on a brain chemical called serotonin, there is a 
theoretical risk that you will develop a condition called serotonin syndrome when you take POMA in 
addition to the antidepressant. We do not know how often this could happen. Serotonin syndrome 
includes high body temperature, agitation, increased reflexes, tremor, sweating, dilated pupils, and 
diarrhea. In its most severe forms it can also cause seizures and an increase in a muscle enzyme called 
creatine phosphokinase in the blood. If you have any symptoms such as the above, we would ask you 
to contact the study doctor as soon as possible as this could be an emergency. 
 
Gadolinium risks:  Gadolinium compounds do have side effects. There are different forms of 
compounds;  we use Dotarem. 
Common side effects of gadolinium: Nausea and vomiting is observed in less than 2% of people 
injected with gadolinium. If you feel nauseous, please alert staff immediately. Dry mouth (less 
than 2%), dizziness (less than 3.6%), and headache (less than 5%) are also possible side effects.  
An additional side effect is hives, observed in less than 1% of people injected with gadolinium. 
All of these side effects resolve within 20 minutes to several hours. People with active asthma, 
allergies, or known sensitivities to contrast agents are at increased risk for more serious side 
effects (less than 1 in 10,000 injections), such as severe allergic reaction that may result in 
sudden difficulty in breathing. Therefore, they will not be injected with Gadolinium.  
Gadolinium can be harmful to someone with kidney disease; so you should not participate in 
this study if you have kidney problems. You will be screened for renal impairment through 
medical history interview and  laboratory blood tests. 
 
The Food and Drug Administration (FDA) has issued an announcement stating they are 
investigating a possible risk of adverse health effects from repeated use of gadolinium for 
MRI. Though the FDA has not reached a conclusion at this time, you should not participate 
in this study if you have previously had more than 1 MRI scan with gadolinium. 
 
The experimental medication you will be taking during the study, POMA, can cause nausea 
and vomiting. The medication administered during the MRI scan, gadolinium, can also 
cause nausea and vomiting. Vomiting inside the MRI scanner could be dangerous because 


For emergency or questions call:                                           
  
Dr. Ragy Girgis at 646-775-5553                                          
   
 
9 
V. 8/20 
of a risk of choking. Therefore, if you feel nauseated or have been vomiting before 
beginning the MRI scan, you should let study staff know and should not have the scan done 
at that time. While you are in the scanner if you begin to feel nauseated, alert the staff right 
away, so that you can be removed from the scanner. 
 
MRI risks: The main risk of MRI is the risk of nausea and vomiting while in the MRI machine, due 
to either the gadolinium or POMA. Vomiting inside the MRI scanner could be dangerous because of 
a risk of choking. Therefore, if you feel nauseated or have been vomiting before beginning the MRI 
scan, you should let study staff know and should not have the scan done at that time. While you are 
in the scanner if you begin to feel nauseated, alert the staff right away, so that you can be removed 
from the scanner. 
 
While there have been no reports of any harmful long-term effects caused by 3T magnets or 
magnets of even higher strength, the long-term effects of being placed in a magnet of this strength 
are unknown. Also, although there are no known risks associated with pregnancy,  we will not scan 
someone who is pregnant. If you are a female in your childbearing years, you will be asked to take a 
pregnancy test to ensure that you are not pregnant. Some people have reported sensations during 
MRI scans with the 3T magnet, such as "tingling" or "twitching" (or, very rarely, a painful 
sensation), which are caused by changes in the magnetic field that can stimulate nerves in your 
body. With any MRI scan, on occasion, some people experience nervousness or discomfort due to 
the scanner's small space and the need to lie still. Except for pacemakers, some types of metallic 
implants, and medication patches, we are not aware of any other potentially dangerous interactions 
or hazards associated with the MRI scan. The MRI scanner also produces a loud noise; earplugs will 
be provided to reduce this discomfort. If you experience any discomfort and wish to stop the scan, 
you can push a button to tell the MRI technologist, and he or she will stop the scan immediately. 
 
Blood draw/IV risks: The needle stick of the blood draw and brain imaging I.V. may cause mild 
pain, bleeding at the site, bruising, dizziness, and, in rare cases, infection. The total amount of 
blood drawn in the study will be approximately 3 tablespoons. 
Pregnancy risks: The procedures of this study including MRI, gadolinium, and taking POMA, are 
not considered safe during pregnancy or breast-feeding, because there is concern about causing 
permanent damage to a developing fetus or young infant (for example, birth defects, or problems 


For emergency or questions call:                                           
  
Dr. Ragy Girgis at 646-775-5553                                          
   
 
10 
V. 8/20 
that emerge during infancy or childhood), such as abnormal bone development. Therefore, you 
should not participate in this research if you are pregnant, or breast feeding a baby, or if you plan to 
become pregnant during the time you are in the study. 
COVID-19 risks:  Going out in public and traveling involves some risk of infection with COVID-19. 
There is risk of COVID-19 infection during in-office visits and during travel for research purposes.  
This risk can be reduced by taking recommended precautions. These include always wearing a mask 
in public and while traveling, practicing hand hygiene, and staying at least 6 feet away from others. 
If you do not feel comfortable traveling to the medical center for an appointment, for example if the 
subway or bus you would normally take is crowded, you can reschedule, or we may be able to 
arrange alternative transportation. We have also minimized in-office visits to lessen this risk. 
We will keep you informed about current public health recommendations, such as federal and local 
government guidelines and directives. 
To determine your eligibility for this study, a pregnancy test will be conducted before you enter the 
study. If the test is positive, you will not be able to participate in the study. Pregnancy tests will be 
repeated before every MRI during the study as well as on the first visit before you receive POMA 
and on Day 7. It is important to understand that even if a pregnancy test is negative, you could still 
be pregnant, because these tests cannot detect very early pregnancies (that is, within the first few 
days). If you are sexually active, it is very important that you use an effective form of birth control 
before and throughout your study participation. Methods of birth control considered to be effective 
include: double barrier methods (condom plus spermicide, or diaphragm plus spermicide), IUDs or 
intrauterine devices, birth control pills, injectable hormones, or if your partner has a vasectomy. It is 
important to understand that even if you use an effective birth control method, there is still a chance 
you could become pregnant. Also, if you do not use the birth control method consistently (for 
example if you don’t use condom/spermicide some of the time) you may become pregnant. If you 
think you might be pregnant, it is important to let the study team know right away. The study team 
will conduct a pregnancy test and help you decide what to do next.  
For males: Because the risks of POMA on male reproductive safety are not known, you must use an 
effective form of birth control during this study. Methods of birth control considered to be effective 
for males are condoms, condoms with spermicide, and vasectomies. If you are sexually active, it is 
very important that you use an effective form of birth control before and throughout your study 
participation. 


For emergency or questions call:                                           
  
Dr. Ragy Girgis at 646-775-5553                                          
   
 
11 
V. 8/20 
Research Interview risks: The research interviews and testing are time consuming and deal with 
personal matters. If at any time you feel upset, tired or anxious, you can choose not to answer 
specific questions. You can also ask to have the interview stopped at any time. 
 
Benefits 
This study was not designed for your benefit. We do not expect that you will notice any changes 
during the study. If you do feel better during the study, we don’t expect it will last after you finish the 
study. Your participation will provide important information about the safety and action of POMA 
on brain regions and people may benefit from the information learned from the results of this study. 
 
Results of your MRI   
 While MRI scans are sometimes done for clinical purposes, the kind of MRI scan you will have as 
part of this study is for research purposes only.  This means that the scans are not designed to 
provide clinical information that might be helpful to you or your doctor and they may not show 
problems that would normally be found in an MRI ordered to evaluate a specific medical problem.  
It is likely that the MRI scan will not have the quality of those done for clinical purposes.  
However, within 7 days of the MRI, the scan will be read by a neuroradiologist for evidence of any 
obvious irregularities requiring your follow-up.  You, or a physician whom you may designate, will 
be informed only when significant abnormalities are detected.  If you wish, we can also inform you 
if there were no obvious findings.  Given the nature of the scan, the absence of a finding does not 
mean that one is not present. 
 
Compensation 
If you participate in the study, you will receive $50 per study visit, which is up to three study visits 
for screening, as well as the Day 7 and Day 14 study visits (5 total). You will also receive $150 for 
each of the brain imaging sessions (up to 2 total). You may receive compensation reasonable for 
local travel expenses 
 
Therefore, the total estimated compensation if you participate in the study is $550. If you agree to 
come in as a standby subject, you will receive a check for $50. If you come in as a standby subject 
and are asked to participate in the scanning procedures, you will be paid according to the protocol. 
If you come in as a standby subject multiple times, you will be paid $50 for each visit. 


For emergency or questions call:                                           
  
Dr. Ragy Girgis at 646-775-5553                                          
   
 
12 
V. 8/20 
 
You will be paid by cash or check. If you are paid by check, you will receive a check in 4-6 weeks 
from that study visit. 
 
We are required by law to report your earnings to the IRS. Therefore, your Social Security Number 
and amount earned will be reported and you will receive the appropriate IRS form at the end of the 
year in which you have been paid. No information about which study you have participated in or 
anything else about this study will be provided to the IRS. Please note that payment for this study may 
affect entitlements/benefits that you receive, such as Medicaid, Social Security, and other city and state 
support services. 
 
Confidentiality All written information acquired in this study will be stored in locked files, accessible 
only the researchers directly involved in this study. All computer-stored information (such as the MRI 
images) will be "coded"—labeled only with a code. These code numbers will not use a name or any 
other identifying feature, and will be randomly assigned to the MRI images.  The brain imaging data 
contains only the coded number, and does not contain the person’s name, initials, date of birth, sex, or 
other personally-identifying information.  The link between a person's identity and the code number 
will be stored in locked files, accessible only to the researchers directly involved in this study. When 
the results of this study are published or presented, no information which could identify you will be 
used.  The results of your MRI scan will be maintained in an electronically secure database at NYSPI 
or CUMC and be accessible only to the members of the research team. The coded brain imaging data 
will be shared amongst investigators at NYSPI and CUMC for purposes of brain imaging data analysis.   
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 for the whole study. You can search this web site at any time. 
In addition to the confidentiality protections described in this consent form, a federal law called the 
Genetic Information Nondiscrimination Act (GINA) generally makes it illegal for health insurance 
companies, group health plans, and most employers to discriminate against you based on your genetic 
information. GINA does not protect you against genetic discrimination by companies that sell life 
insurance, disability insurance, or long-term care insurance or by adoption agencies. GINA also does 
not protect you against discrimination based on an already diagnosed genetic condition or disease. If 
you would like to know more about it you can discuss this with the principal investigator of this study 


For emergency or questions call:                                           
  
Dr. Ragy Girgis at 646-775-5553                                          
   
 
13 
V. 8/20 
or you can go to the following website www.genome.gov/10002328. This study will not include whole 
genome sequencing. 
Additionally, the Food and Drug Administration (FDA) may inspect the records for this study. 
This research is covered by a Certificate of Confidentiality issued by the Department of Health and 
Human Services (DHHS). The researchers with this Certificate may not disclose or use information, 
documents, or biospecimens that may identify you in any federal, state, or local civil, criminal, 
administrative, legislative, or other action, suit, or proceeding, or be used as evidence, for example, if 
there is a court subpoena, unless you have consented for this use. Information, documents, or 
biospecimens protected by this Certificate cannot be disclosed to anyone else who is not connected 
with the research except, if there is a federal, state, or local law that requires disclosure (such as to 
report child abuse, intent to harm self or others, or communicable diseases, but not for federal, state, or 
local civil, criminal, administrative, legislative, or other proceedings, see below); if you have 
consented to the disclosure, including for your medical treatment; or if it is used for other scientific 
research, as allowed by federal regulations protecting research subjects. 
You should understand that a Certificate of Confidentiality does not prevent you or a member of your 
family from voluntarily releasing information about yourself or your involvement in this research. If an 
insurer, employer, or other person obtains your written consent to receive research information, then 
the researchers may not use the Certificate to withhold that information. 
This Certificate cannot be used to refuse a request for information from personnel of the United States 
federal or state government agency sponsoring the project that is needed for auditing or program 
evaluation by the organization which is funding this project or for information that must be disclosed 
in order to meet the requirements of the federal Food and Drug Administration (FDA). Records will be 
available to research staff, and Federal, State and Institutional regulatory personnel (who may review 
records as part of the routine audits). 
Any information obtained as part of this study, including biospecimens, may be used in future research 
studies or distributed to another investigator for future research studies, but will not include any 
information that can identify you. 
When conducting remote visits, we will use telephone or HIPAA compliant video conferencing. 
Data Sharing 
A data repository has been created by the National Institute of Mental Health (the funding agency for 
this study) that allows sharing of research data and scientific collaboration. The data repository is 
accessible only to qualified investigators. All subject data will be de-identified (your name will not be 
used) and each subject will have a separate identifier called a Global Unique Identifier (GUID) to 
remove any possibility that the data can be linked directly to you. The GUID is a universal subject ID 
that allows researchers to share data specific to a study participant without exposing personally 
identifiable information (PII). All subjects in this study will be assigned a GUID. The following 
information will be collected and entered into the study database to generate a GUID: First name, 
Last name, Middle name (if applicable), Month of birth, Day of birth, Year of birth, Physical sex at 


For emergency or questions call:                                           
  
Dr. Ragy Girgis at 646-775-5553                                          
   
 
14 
V. 8/20 
birth, and Name of city/municipality of birth. Once the GUID is generated, all personal information 
will be deleted from the study database. 
 
During and after the study, the researchers will send deidentified information about your health and 
behavior and in some cases, your genetic information, to NDCT (National Database for Clinical 
Trials), which is a national database for information from clinical trials that are sponsored by the 
government/NIMH. Other researchers nationwide can then file an application with the NIMH to 
obtain access to your deidentified study data for research purposes. Experts at the NIMH who know 
how to protect health and science information will look at every request carefully to minimize risks to 
your privacy. 
 
You will not benefit directly from allowing your information to be shared with NDCT. 
However, the information provided to NDCT may help researchers around the world treat future 
children and adults with mental illnesses so that they have better outcomes. NIMH will also report to 
Congress and on its web site about the different studies that researchers are conducting using NDCT 
data. However, you will not be contacted directly about the data you contributed to NDCT. 
 
You may decide now or later that you do not want to share your information using NDCT. If so, 
contact the researchers who conducted this study, and they will tell NDCT, which can stop sharing 
the research information. However, NDCT cannot take back information that was shared before you 
changed your mind. If you would like more information about NDCT, this is available online at 
http://ndct.nimh.gov. 
 
The data from this study may also be shared with the company that makes POMA (DeNovo). Any data 
that will be shared with them will be deidentified, meaning it will have no information that would be 
able to identify you. The company may use these data for commercial profit that you would not share 
in. 
We will tell you about any clinically relevant research results, including individuals research results, 
such as results of blood laboratory values or MRI results. We can also share this information with a 
physician of your choice. 
Risks to Privacy: As in any research study, it is possible that personal information about you could 
become known to other people. The investigators will take precautions to prevent this from happening. 
Your name will not appear on any questionnaires or test that you complete during the study. Instead, 
all questionnaires and tests you complete will be coded with a study code number. 
 
Questions 
The investigators will answer to the best of their ability any questions that you may have about the 
procedures or your response to them. You can contact the Principal Investigator, Dr. Scott Small at 


For emergency or questions call:                                           
  
Dr. Ragy Girgis at 646-775-5553                                          
   
 
15 
V. 8/20 
(646) 774-5553 if you have any questions about the study now or in the future.  If you have any 
questions about the rights of research participants or complaints, you may call the NYSPI IRB Main 
Office at (646) 774-7155 during business hours. An IRB is a committee that protects the rights of 
human subjects in research studies. 
 
Compensation for Research Related Injuries 
Federal regulations require that research participants be informed about our institutions’ policies with 
regard to the provision of treatment and compensation for research related injuries.  If you believe you 
have sustained an injury as a result of participating in this research study, you should contact the Dr. 


For emergency or questions call:                                           
  
Dr. Ragy Girgis at 646-775-5553                                          
   
 
16 
V. 8/20 
Girgis, at (646) 774-5553, or the NYSPI IRB Main Office at (646) 774-7155 so that you can review 
the matter and identify medical resources that may be available to you. 
 
Please be aware that: 
a. New York State Psychiatric Institute, New York Presbyterian Hospital, and the Columbia University 
Medical Center will each furnish that emergency medical care and assistance in arranging follow up 
care determined to be necessary by its medical staff. 
b. You will be responsible for the cost of such care, either personally or through your medical 
insurance or other form of medical coverage. 
c. No monetary compensation for wages lost as a result of injury will be paid to you by New York 
State Psychiatric Institute, New York Presbyterian Hospital, Research Foundation for Mental Hygiene, 
or by Columbia University Medical Center. 
d. By signing this form, you are not waiving any of your legal rights to seek compensation through the 
courts. 
 
___ 
 
I am planning on having a gadolinium MRI scan within the 2 weeks before the 
study, during the study, or within 2 weeks after the study. 
 
___ 
 
I am not planning on having a gadolinium MRI scan within the 2 weeks before the 
study, during the study, or within 2 weeks after the study. 
 
********************************************************************************** 
 
___ 
 
I agree to being considered as a Stand by subject. 
 
___ 
 
I do not want to be considered to be a Stand by subject. 
 
You will be given a copy of this consent form to keep. 
 


For emergency or questions call:                                           
  
Dr. Ragy Girgis at 646-775-5553                                          
   
 
17 
V. 8/20 
 
Documentation of Consent 
 
I voluntarily agree to participate in the research study described above. 
Name of Participant                                                                      
 
Signature of Participant                                                               Date                               
 
Statement of the Investigator (Must be M.D.) 
 
I have discussed the proposed research with this patient, and, in my opinion, the patient 
understands the benefits, risks and alternatives (including non-participation) and is capable of 
freely consenting to participate in this research. 
 
Printed Name                                                                      
 
Signature                                                                            Date                                 
 
Independent Assessment of Capacity 
 
I have examined                                                   on                             for the purpose of determining 
whether he/she is capable of understanding the purpose, nature, risks, benefits and alternatives 
(including non-participation) of the research, making a decisions about participation, and 
understanding that the decision about participation in the research will involve no penalty or loss of 
benefits to which the patient is otherwise entitled, for Dr. Scott Small’s research project “Glutamate 
reducing interventions in schizophrenia”. 
 
On the basis of this examination I have arrived at the conclusion that: 
 
        A.  This patient has this capacity at this time. 
 
      B.  There is a question about this patient’s capacity at this time. 


For emergency or questions call:                                           
  
Dr. Ragy Girgis at 646-775-5553                                          
   
 
18 
V. 8/20 
 
      C.  This patient clearly lacks this capacity 
 
Printed Name                                               
 
Date                              
 
Signature                                                      
(Member of treatment team; MD or PHD; Not a member of the research staff) 

Prot_000.pdf: 
Protocol Summary Form
7459
Small, Scott
Page 1 of 27
Protocol Title:
Glutamate Reducing Interventions in 
Schizophrenia
Protocol Number:
7459
First Approval:
06/15/2017
Expiration Date:
06/04/2021
Version Date:
08/24/2020
Clinic:
Center of Prevention and Evaluation 
(COPE)
Contact Principal Investigator:
Scott Small
Email: sas68@columbia.edu
Telephone: 2123051269
Co-Investigator(s):
Jeffrey Lieberman, MD
Ragy Girgis, MD
Research Chief:
Lawrence Kegeles, MD
Cover Sheet
Choose ONE option from the following that is applicable to your study
If you are creating a new protocol, select "I am submitting a new protocol." As 5 Year Renewals are no 
longer required, this option remains for historical purposes.
I am proposing an amendment only to an existing protocol
Division & Personnel
Division
What Area Group does the PI belong to?
What Division/Department does the PI belong to?
Translational Imaging
Within the division/department, what Center or group are you affiliated with, if any? 
COPE
Unaffiliated Personnel
List investigators, if any, who will be participating in this protocol but are not affiliated with New York 
State Psychiatric Institute or Columbia University. Provide: Full Name, Degrees and Affiliation.


Protocol Summary Form
7459
Small, Scott
Page 2 of 27
na
Amendment
Describe the change(s) being made 
We are submitting this amendment to revise this protocol to include that research staff will monitor each 
dose of POMA taken by participants via hipaa compliant video. We are doing this because an initial analysis 
of PK data indicated substantial nonadherence with POMA. We made this change to the PSF (Study 
Procedures, in bold, towards the end) and the CF (page 4, bolded). We are also changing the time of the PK 
blood draws from pre dose on days 7 and 14 to 2-3 hours after the dose on day 7 and right before the MRI 
on day 14 (Study Procedures, in bold, towards the end). We are making this change
because the half life of POMA is only a few hours and we think that peak rather than trough levels will be 
more informative. We have included clean and bolded versions of the patient CF.
Provide the rationale for the change(s) 
Please see above.
Comment on the extent to which the proposed change(s) alter or affect risks/benefits to subjects 
Please see above
Comment on if the proposed change(s) require a modification to the Consent Form (CF)
Please see above. Yes, a change was made.
Procedures
To create the protocol summary form, first indicate if this research will include any of the following 
procedures
   Neuropsychological Evaluation
   Collection of Biological Specimens
   Medication Trial
   Use of Placebo or Sham Treatment
   MRI
   Use of Investigational Drug or Device
   Internet-based Data Collection or Transmission
Population
Indicate which of the following populations will be included in this research
   Adults who may have impaired decision-making ability
   Medically and Psychiatrically Healthy Subjects
   Adults


Protocol Summary Form
7459
Small, Scott
Page 3 of 27
Research Support/Funding
Will an existing internal account be used to support the project?
No
Is the project externally funded or is external funding planned?
Yes
Select the number of external sources of funding that will be applicable to this study
Funding Source #1
Is the PI of the grant/contract the same as the PI of the IRB protocol? 
Yes
Select one of the following
The grant/contract is currently funded
Source of Funding
Federal
Institute/Agency
NIMH
Grant Name
Glutamate reducing interventions in schizophrenia
Grant Number
R61 MH112800-01
Select one of the following
Single Site
Business Office
CU
Does the grant/contract involve a subcontract? 
Yes
Subcontracted?
To
Name institution(s)
RFMH, Dr. Lieberman is the PI of the RFMH Subcontract
Study Location
Indicate if the research is/will be conducted at any of the following
   NYSPI
This protocol describes research conducted by the PI at other facilities/locations
No
Lay Summary of Proposed Research 


Protocol Summary Form
7459
Small, Scott
Page 4 of 27
Lay Summary of Proposed Research
Previous research suggests that elevations of a brain chemical called glutamate can lead to an increased risk 
for developing schizophrenia. If this research is correct, then medications that decrease glutamate may be 
able to prevent the development of schizophrenia. One medication that decreased brain glutamate is a 
medication called pomaglumetad (POMA). POMA has been tried several times in schizophrenia but without 
much success. We think that this may be because these people already had schizophrenia. In addition, the 
people who did these studies used doses of POMA that were too low and did not actually decrease 
glutamate. Third, the people who did these studies did not use a brain imaging method of measuring 
whether or not POMA affected glutamate levels in the brain.
 
 To address these limitations of prior studies, we will administer several doses of POMA (low and high 
doses) over 14 days to individuals at clinical high risk for developing psychosis and use MRI brain imaging 
to  determine whether these doses of POMA are affecting glutamate levels. In a second phase, we will use 
the dose of POMA that is found to decrease glutamate levels in a clinical trial in which we compare that 
dose of POMA with placebo in a standard clinical trial.
 
We will also perform a study to examine the stability of our MRI measures over up to 4 months in a 
healthy control population.
Background, Significance and Rationale
Background, Significance and Rationale
Studies suggest that abnormal elevations in extracellular glutamate can act as a pathogenic driver of
schizophrenia, including in the hippocampus a brain region that neuroimaging studies suggest might be
affected first and foremost. If this formulation is correct, then high glutamate should be considered a 
molecular target for drug discovery and agents that reduce extracellular glutamate should be an effective 
intervention. Pomaglumetad methionil (which we will call ‘POMA’) is one such agent, because as an 
agonist of presynaptic metabotropic glutamate 2/3 receptors this class of drug has been found to reduce 
glutamate release. Nevertheless, trials that have used POMA have to date shown little efficacy in patients 
with schizophrenia. Despite these failures, we believe that, based on the accumulative evidence, high 
glutamate is indeed a valid target and that two reasons might account for these initial failures. First, as these 
trials did not use a reliable brain biomarker of glutamate elevations there was no readout of ‘target 
engagement’, and thus it remains possible that these trials were false negatives. Second, and more 
importantly, schizophrenia is now thought to start in a prodromal phase before the onset of psychosis, and 
there is evidence to suggest that the prodromal stage might represent a unique time-window for therapeutic 
interventions, and so it possible that the drug was given at the wrong stage of the disease.
 
Pathophysiological support for these conclusions comes from our studies (Schobel et al, Neuron, 2013)
in which we applied fMRI indicators of metabolism and volumetric MRI to patients in prodromal stages of 
the disease who then progressed to the psychotic stage, and to a mouse model of the disease. Collectively, 
these studies suggested that glutamate is a driver of hippocampal dysfunction, that fMRI measures are 
sensitive to glutamate elevations, and that glutamate-reducing drugs can ameliorate hippocampal 


Protocol Summary Form
7459
Small, Scott
Page 5 of 27
dysfunction. We also have completed preliminary studies using magnetic resonance spectroscopy, in which 
we show that hippocampal glutamate is elevated in prodromal stages of the disease.
 
Based on the results of these and other studies, we have recently proposed a mechanistic model of
disease progression (Small, Neuron, 2014), which predicts that because of its distinct pathophysiological 
features the prodromal stage of disease is a unique time-window that is most amenable to glutamate-
reducing interventions. This mechanistic model motivates this protocol in which we hypothesize that: 1) 
MRI based measures of hippocampal metabolism and glutamate can be used as in vivo biomarkers of target 
engagement when using a glutamate-reducing intervention. 2) Glutamate-reducing interventions will be 
most effective when administered to prodromal patients, and only when they are shown to engage their 
target. The R61 phase of this proposal is designed to test the first hypothesis, and the R33 phase is designed 
to the second. The current IRB describes the R61 phase.
 
We will also perform a study to examine the stability of our MRI measures over up to 4 months in a 
healthy control population. 
Specific Aims and Hypotheses
Specific Aims and Hypotheses
To perform a double-blind, randomized, phase Ib, multiple dose trial of 14 days of treatment with POMA 
(40mg bid, 80mg bid, 120mg bid, 160mg bid) in clinical high risk patients to determine which dose, if any, 
reduces hippocampal glutamate and metabolism using MRI techniques. The GO NO-GO decision will be 
whether or not any dose tested in the R61 phase of the trial decreases left CA1 CBV.
 
To examine the stability of our MRI measures over up to 4 months in a healthy control population. 
Description of Subject Population
Sample #1
Specify subject population
Clinical High Risk
Number of completers required to accomplish study aims
12
Projected number of subjects who will be enrolled to obtain required number of completers
50
Age range of subject population
18-30


Protocol Summary Form
7459
Small, Scott
Page 6 of 27
Sample #2
Specify subject population
Controls
Number of completers required to accomplish study aims
20
Projected number of subjects who will be enrolled to obtain required number of completers
30
Age range of subject population
18-30
Gender, Racial and Ethnic Breakdown
33% Caucasian, 33% African American, 10% Asian, 24% Mixed; 33% Hispanic; 70% male, 30% female
Description of subject population
As above
Recruitment Procedures
Describe settings where recruitment will occur
Patients will be told about the study by staff at the COPE clinic (IRB #6654R). If they are interested, they 
will then be referred to study investigators designated to obtain informed consent, who will describe the 
study in greater detail and then obtain informed consent. Specifically, patients interested in participation will 
be screened by study physicians and told about the study. They will be told about the procedures and risks, 
that the study involves randomization and the details will be explained. They will also be told that 
participation is voluntary, and of the extra study details beyond that of the COPE protocol itself and 
affiliated observational studies, including exposure to POMA and gadolinium contrast. If interested and 
eligible, patients will have an evaluation of their capacity to consent and invited to provide written informed 
consent.
 
Healthy control subjects will be recruited through #6654R as well as from other Area Psychosis 
research studies that include healthy control subjects who have expressed interest in additional 
research.
How and by whom will subjects be approached and/or recruited? 
See above. All patients will be initially recruited through 6654R.
How will the study be advertised/publicized? 
As above. Patients are initially recruited through 6654R.
Do you have ads/recruitment material requiring review at this time? 
No
Does this study involve a clinical trial?
Yes
Please provide the NCT Registration Number


Protocol Summary Form
7459
Small, Scott
Page 7 of 27
NCT03321617
Concurrent Research Studies
Will subjects in this study participate in or be recruited from other studies? 
Yes
Describe concurrent research involvement
Subjects may also be active in IRB #6654R, 7132R, 7342 (PI Girgis on them all) as they are longitudinal 
studies. However, no study procedures for the other studies will take place while active in the current study. 
Rather, the other studies are studies which involve an active period, followed by up to two years of 
longitudinal follow up before procedures are repeated (6654R is the screening/umbrella protocol for all 
COPE studies). Therefore, subjects will not actually be "active" in more than one study while part of the 
current study, and therefore subjects will finish this study before moving on to any other studies. Patients 
will be told about the study by staff at the COPE clinic (IRB #6654R). If interested, the study will be 
explained in greater detail by a study physician. Healthy control subjects may also be recruited through 
6654R or other Area Psychosis research studies though will only be active in one protocol at a time.
Inclusion/Exclusion Criteria
Name the subject group/sub sample
Clinical High Risk
Create or insert table to describe the inclusion criteria and methods to ascertain them
Criterion
Method of Ascertainment
1. COPE Patient between the ages of 18-30 
(Identified as at clinical high risk for psychosis 
as defined as a) attenuated psychotic symptoms; 
or b) brief intermittent psychotic symptoms c) 
schizotypal disorder or family history of 
psychotic disorder with
recent decline in functioning (30 GAF points))
Structured Interview for Prodromal Syndromes/ 
Scale of Prodromal Symptoms (SIPS/SOPS)
2. Capacity to provide informed consent 
Clinical assessment by research team and 
independent assessment of capacity
3. Currently using a reliable form of birth 
control (females and males)
Physician interview
 
 
 
Create or insert table to describe the exclusion criteria and methods to ascertain them
 


Protocol Summary Form
7459
Small, Scott
Page 8 of 27
 
Criterion
Method of Ascertainment
1. Metal implants in body or a history of metal 
working
Physician evaluation
2. Lifetime diagnosis of asthmatic symptoms 
within the past 3 years or known sensitivity to 
contrast agents
Physician evaluation
3. Lifetime diagnosis of renal failure/disease
Physician eval and laboratories
4. Acute neurological, neuroendocrine, or 
medical disorder including renal insufficiency 
(CrCl <60mL/min/1.73m2
Physician exam, electrolytes, CBC
5. Lifetime diagnosis of hypertension or diabetes 
or seizure disorder
Physician evaluation
6. IQ < 70
WTAR < 6
7. Acute risk for suicide and/or violence
Physician evaluation, suicidal or violent act in 
last 6 months, CSSRS
8. Pregnant, lactating
Urine pregnancy test
9. Current abuse of substances (alcohol, cocaine, 
stimulants, cannabis, opiates, sedative 
hypnotics)
SCID, utox
10. Current use or anticipated need for any 
antipsychotics or mood stabilizers (all 
antipsychotics, also Depakote, lithium, 
lamotrigine, pregabalin or any med with a 
mechanism of action like gabapentin) 
probenecid. Patients may take selective 
serotonin reuptake inhibitors, tricyclic 
antidepressants, and monoamine oxidase 
inhibitors as long as they have been on a 
stable dose for at least 4 weeks before starting 
study drug.
Physician Eval
11. More than one previous gadolinium scan
Physician Eval
 
 
 
 
Inclusion/Exclusion Criteria #2
Name the subject group/sub sample
Controls


Protocol Summary Form
7459
Small, Scott
Page 9 of 27
Create or insert table to describe the inclusion criteria and methods to ascertain them 
 
 Criterion  
 Method of Ascertainment
 1. Healthy control between the ages of 18-30  Scid
 2. Capacity to provide informed consent
 Clinical assessment by 
research team
 3. Currently using a reliable form of birth 
control (females)
 physician interview
 
 
 
 
Create or insert table to describe the exclusion criteria and methods to ascertain them 
 
 
 Criterion
 Method of 
Ascertainment
 1. Metal implants in body or a history of metal 
working
 metal screener
 2. Any neurological disorder
 medical history
 3. IQ < 70
 WTAR < 6 (only if 
IQ < 70 is suspected)
 4. Pregnant, lactating
 urine pregnancy test
 5. Current use of substances (cocaine, stimulants, 
cannabis, opioids, sedative hypnotics)
 utox, SCID
 6. Any history of use of a psychiatric medication
 History
 7. Any history of a DSM Axis I disorder with the 
exception of specific phobias and adjustment 
disorders
 SCID
 
 
 
 
 
Waiver of Consent/Authorization


Protocol Summary Form
7459
Small, Scott
Page 10 of 27
Indicate if you are requesting any of the following consent waivers
Waiver of consent for use of records that include protected health information (a HIPAA waiver of 
Authorization) 
No
Waiver or alteration of consent
No
Waiver of documentation of consent 
Yes
Waiver of parental consent 
No
Consent Procedures
Is eligibility screening for this study conducted under a different IRB protocol?
Yes
Indicate NYSPI IRB # 
6654R
Describe Study Consent Procedures
Patients will be told about the study by staff at the COPE clinic (IRB #6654R). If they are interested, they 
will then be referred to study investigators designated to obtain informed consent, who will describe the 
study in greater detail and then obtain informed consent. Specifically, patients interested in participation will 
be screened by study physicians and told about the study. They will be told about the procedures and risks, 
that the study involves randomization, and the details will be explained. They will also be told that
participation is voluntary, and of the extra study details beyond that of the COPE protocol itself and 
affiliated observational studies, including exposure to POMA and gadolinium contrast. If
interested and eligible, patients will have an evaluation of their capacity to consent and invited to
provide written informed consent. We will explicitly ask all subjects if they are planning on having a 
gadolinium MRI scan within the 2 weeks before the study, during the study, or within 2 weeks after the 
study (we will place this in the consent form).
 
 Control subjects will be similar told about the study and consented if they are interested. Controls will not 
require an independent assessment of capacity.
 
Remote/virtual Procedures: remote procedures will be similar to in person procedures except that we 
will use redcap to obtain signed consent (using the e signature feature) on the consent forms and 
hipaa forms. This may occur by either phone or video. If a subject is unable to use redcap for some 
reason, we will use a verbal consent procedure. When a verbal consent procedure is done by phone, 
CFs and HIPAA forms will be sent to participants, preferably in advance in possible, for their review 
and records (but not signed). We have requested a Waiver of Documentation of Consent in the 
Waiver section of the PSF. In these cases, a note-to-file will be added to the participant’s chart on the 
date of the verbal consent procedure documenting the consent discussion and the participant’s verbal 
consent, signed by the consenter.
 


Protocol Summary Form
7459
Small, Scott
Page 11 of 27
We are confirming that the consent discussion process will include discussion of the technology 
HIPAA-compliant platforms to be used and any concerns the patient may have, such as access to a 
private space in which to take calls, or accessibility—access at home to adequate devices, cell signal, 
or wifi.
We are also confirming that the consent discussion includes the of risks of possible loss of 
confidentiality with remote procedures, as well as the risk of attending the MRI or any other 
procedure in-person during the pandemic, and how these risks can be mitigated.
 
Indicate which of the following are employed as a part of screening or main study consent procedures
   Consent Form
   Information Sheet
Waiver of Documentation of Consent
Would the consent form signature be the only link between the subject’s identity and the research data?
No
Is breach of confidentiality the main study risk?
No
Is consent for this research procedure ordinarily not required outside of the research context? Explain
For our remote/virtual consent procedures, we will use redcap. If a subject is unable to use redcap for 
some reason, we will use a verbal consent procedure. When a verbal consent procedure is done by 
phone, CFs and HIPAA forms will be sent to participants, preferably in advance in possible, for their 
review and records (but not signed). We have requested a Waiver of Documentation of Consent in the 
Waiver section of the PSF. In these cases, a note-to-file will be added to the participant’s chart on the 
date of the verbal consent procedure documenting the consent discussion and the participant’s verbal 
consent, signed by the consenter. We are requesting the waiver of documentation of consent because, 
in this case, we do not want subjects to send us PHI when it may not be sent in a private manner.
Persons designated to discuss and document consent
Select the names of persons designated to obtain consent/assent
Girgis, Ragy, MD
Lieberman, Jeffrey, MD
Small, Scott
Type in the name(s) not found in the above list
Independent Assessment of Capacity


Protocol Summary Form
7459
Small, Scott
Page 12 of 27
You have indicated that your study involves subjects who MAY LACK capacity to consent.
Does this study require an independent assessment of capacity?
Yes
Methods/procedures for capacity assessment
Capacity will be assessed by a psychiatrist or psychologist licensed in NY state and who is not associated 
with this study (patients only).
Study Procedures
Describe the procedures required for this study
a. COPE patients (IRB #6654R) Patients will be told about the study by staff at the COPE clinic (IRB
#6654R). If interested, the study will be explained in greater detail by a study physician. Patients will
provide written informed consent and capacity determined by a licensed, CITI trained MD or PhD
psychologist at NYSPI.
b. Baseline measures (pre-randomization):
i. Serum laboratory tests (beta HCG if female, electrolytes, serum BUN/creatinine, CPK, urinalysis, liver 
function tests, CBC with differential, thyroid function tests); If eGFR <40 mL/min/1.73m2 or serum 
pregnancy test positive , then patients will discontinue the study (exclusion criterion for exposure to 
gadolinium.
ii.a urine toxicology screen
iii. general physical exam, including measures of weight, blood pressure, temperature pulse, respiration, 
EKG.
iv. 5cc of blood for DNA analysis
c. Structural Interview of Prodromal Syndromes (SIPS) to evaluate current prodromal symptoms at time of 
study entry
d. SCID to evaluate current psychiatric diagnoses including present of substance abuse
e. MATRICS, Hollingshead, GFS scales, GAF, CGI, SAFTEE, AIMS, CSSRS, Simpson Angus Scale
f. MRI with gadolinium contrast and MRS (one hour). All scans will be examined at the image console for 
gross structural abnormalities such as the presence of mass effects, hydrocephalus, and vascular
malformations by study imager and study physician. Since the images obtained in this study are exclusively 
T-1 weighted, they will not be clinically read, except for screening for gross structural brain abnormalities 
by neuroradiologist within 7 days of the scan. Should there exist a gross structural brain abnormality, a 
neuroradiologist will immediately inform the principal investigator. The neuroradiologist will immediately 
provide an oral report followed by a handwritten or typed note to the PI and the Director of the MRI Unit. A 
final written transcript of the clinical reading will be provided
within two weeks of the oral report. The subject will be informed of the result, post-scan acquisition, by the 
study PI. Appropriate follow-up with the patient’s primary care physician or appropriate sub-specialist and 
care setting will be immediately arranged for further diagnostic testing/treatment recommendations by study 
PI in consultation with the neuroradiologist.
Concomitant Medications: During the trial, no new concomitant psychotropic medications will be permitted 
of the following classes of medication: antipsychotic or mood-stabilizing medication. Antidepressant and 
antianxiety medication, if needed for clinical management, will be allowed, including lorazepam up to 1 mg 
daily (hypnotic, or for anxiety) if needed on a PRN basis. If a patient does require lorazepam, they will not 
take it for 24 hrs prior to MRI scan. If a study participant requires an excluded medication during the course 


Protocol Summary Form
7459
Small, Scott
Page 13 of 27
of the study, they will be discontinued from administration of the POMA, though complete all other study 
procedures. Other medications that do not interact adversely with POMA will not be changed during the 
study.
Treatment Design: Enrollment, randomization, blinding, and assessments for safety
 
Patients will be randomized in a double blind manner to 40mg bid, 80mg bid, 120mg bid, or 160mg bid of 
POMA. They will be randomized in a 1:1:1:1 ratio. The identity of medications will be blinded having 
every subject take an equal number of pills (e.g., someone taking 160mg bid will take 4 tablets of 40mg 
POMA bid, and someone taking 40mg bid will take 1 tab of 40mg POMA bid and 3 identical looking tablets 
of placebo bid). To minimize risk of nausea, we will taper medications up so that on day 1 subjects will take 
40mg bid, on day 2 80mg bid (if at this dose or higher), on day 3 120mg bid (if at this dose or higher), and 
on day 4 160mg bid.
 
After subjects have completed their baseline procedures, they will be given a 7 day supply of POMA. They 
will return on Day 7 and have all baseline measures as described above, with the exception of the SCID and 
MRI. They will then be given another 7 days of POMA and return on day 14 when they will again receive 
all baseline measures including MRI with gadolinium injection, but not including the SCID and blood for 
DNA Analysis.
 
Medication adherence will be assessed by pill count.
 
Pregnancy Testing
As above, we will obtain a serum HCG at screening, as well as urine HCG before any MRI scan and
on the day that study drug is dispensed if that does not occur on the same day as the first MRI scan.
 
Follow Up
 
We will perform a safety check in call 30 days after study participation. We may repeat the safety 
labs/EKG/physical as necessary after Day 14 if there is a clinical indication to do so.
 
PK Testing
 
We will obtain blood samples for PK testing of POMA on days 7 2-3 hours after the dose and 14 right 
before the MRI scan.
 
Phone Check Ins
 
Study physicians will perform phone check ins between days 1 and 7 and between days 8 and 14. In 
addition, research staff will observe patients taking each of their doses via hipaa compliant video.
 
Stand By
 
We will give all subjects the option of being a standby subject. Standby subjects will be asked to come in on 
a day when a brain scan is scheduled for another participant. If for some reason the original participant does 


Protocol Summary Form
7459
Small, Scott
Page 14 of 27
not complete the imaging procedures, the standby will be asked to participate in the imaging procedures in 
place of that person. If the original participant does complete the imaging procedures, they standby will be 
sent home. We expect that standbys will have to wait between 1-3 hours as a standby participant. Subjects 
can choose to be a standby subject by checking one of the boxes found at the end of the consent form. We 
may ask standbys to be standby subjects multiple times. In addition, we may schedule more than one 
standby for a given day. 
 
We have attached a table that includes a summary of all procedures.
 
This trial will be monitored by a DSMB
 
Healthy Control Test Retest Study
 
Healthy control subjects will be screened with the SCID as well as a urine toxicology and urine pregnancy 
test. Eligible subjects will receive up to 4x1 hour MRI/MRS scans over a 4 month period. MRI scans will be 
done as described above, without gadolinium. Standby procedures will also apply to healthy control 
subjects.
 
Remote Procedures: Some of the visits may be conducted remotely using the telephone or HIPAA-
compliant video teleconferencing. In particular, all procedures that can be done remotely including 
consent, capacity and clinical/behavioral assessments will be done remotely except for the blood draw 
and physical exam which will have to occur separate from MRI since these screening procedures are 
required before we begin the study (technically not required for MRI but we prefer to know if 
someone will be eligible for the study before we have people do MRI; we will submit individual 
exception requests if we want to perform an MRI without having received the results of labs and 
physical exam).
 
I attest to follow the COVID-19 Safety Guidelines for Columbia Psychiatry and NYSPI Re-Entry 
outlined in the NYSPI Director’s June 1st memo, which include but are not limited to: 
• Infection Control/PPE – Guidelines 
• Research participants will only come on-site if absolutely necessary for study procedures. 
• No volunteers/externs on-site during Stage 1. 
• Clinical research teams will screen their participants for COVID symptoms (night before and day of 
onsite visit, documenting this in the chart), and escort them in and out of the building. 
• COVID/COVID-like symptoms in participants will be reported to the IRB via PRISM as an SAE. 
You can upload charts or diagrams if any
Criteria for Early Discontinuation  
Criteria for Early Discontinuation
Subjects will be discontinued from this study for any of the following reasons: a) relapse, defined as an 
increase of > 2 points on the CGI-S at any time point; b) the use of > 3 doses of p.r.n. clinically determined 


Protocol Summary Form
7459
Small, Scott
Page 15 of 27
benzodiazepines or any antipsychotics in a week; c) deemed to be clinically necessary in the opinion of the 
investigator based on laboratory information, physical examination, mental status examination, or any other 
clinical information; d) pregnancy; e) seizure activity. All attempts will be made to obtain end-of-study 
CBV scans and ratings for early discontinuations. The blind will be broken at the end of the study. 
Randomization/blind information will not be given to subjects.
 
 
Patients will be discontinued if they convert to psychosis. If this happens, standard treatment/referral 
procedures (as per #6654R) will be implemented. Namely, if they do not already have a clinician, they will 
be treated in COPE until an appropriate referral can be made.
Blood and other Biological Samples
Please create or insert a table describing the proposed collection of blood or other biological specimens
We will obtain up to 120 cc of blood at screening (safety labs and blood for DNA), day 7 (safety labs and 
POMA PK sample), and day 14 (safety labs and POMA PK sample) for a total of 50 cc over the course of 
the study (~3 tablespoons).
Assessment Instruments
Create a table or give a brief description of the instruments that will be used for assessment
The Structured Clinical Interview for DSM-IV (SCID) (First e al., 2001) 45 min is a structured diagnostic 
interview done at baseline to evaluate potential exclusion criteria for the trial.
 
The Structured Interview for Prodromal Symptoms/ Scale of Prodromal Symptoms (SIPS/SOPS) 30 min
(Miller et al.,1999) will be done at baseline, and on days 7 and 14. It includes the GAF.
 
The Global Functioning Scale: Role (GFS: Role; Niendam, Beraden, Johnson & Cannon, 2006), and The 
Global Functioning Scale: Social (GFS: Social; Auther, Smith & Cornblatt, 2006) 5 min.
 
Clinical Global Impression scale (CGI)-3 minutes measures overall clinical functioning.
Columbia Suicide Severity Rating Scale (CSSRS)-5 minutes assesses for suicidality.
MATRICS-60-90 minutes is a comprehensive measure of cognitive functioning. 
Wechsler Test of Adult Reading (WTAR)-5 minutes is a measure of intelligence.
Simpson Angus Scale (SAS) 5 min measures extrapyramidal symptoms
SAFTEE 5 min is a measure of side effects
Please attach copies, unless standard instruments are used


Protocol Summary Form
7459
Small, Scott
Page 16 of 27
Off label and investigational use of drugs/devices
Choose from the following that will be applicable to your study 
   Drug
Select the number of drugs used in this study
1
Drug #1
Name of the drug 
Pomaglumetad
Manufacturer and other information
Lilly and Denovo
Approval Status
IND is approved
IND#
134867
Who holds the IND/IND sponsor?
IND is held by PI/CU Investigator
Lieberman, Jeffrey, MD
Research Related Delay to Treatment
Will research procedures result in a delay to treatment?
No
Treatment to be provided at the end of the study
If subjects clinically require active treatment for new onset mood syndrome (major depressive or bipolar, 
anxiety symptoms, or psychosis during the study period or screening phase) patients will be immediately 
offered such treatment. Subjects will be ineligible for study participation if they meet any exclusion criteria 
as a result of such clinical developments. Since POMA is an experimental medication, it will not be 
available to subjects at the end of the trial.
 
Patients in this study will continue their usual treatment with their usual psychiatrist and clinician without 
interruption or changes. There is currently no standard best clinical practice (psychotherapeutic or 
psychopharmacologic) for prodromal stages of psychotic disease. Available antipsychotic therapies have 
been studied and are associated with improved prodromal symptoms and lessening of transition to 
psychosis, but are associated with a significant side-effect burden, including EPS, weight gain, and 
hyperlipidemia, amongst other side effects. The evidence for efficacy of cognitive-behavioral interventions 
for prevention of transition to psychosis is also mixed to date.
 
All COPE subjects receive up to 2 years of free, no cost treatment (medication management and therapy), 
though they would have to cover the cost of their medications.


Protocol Summary Form
7459
Small, Scott
Page 17 of 27
Clinical Treatment Alternatives
Clinical treatment alternatives
If subjects clinically require active treatment for new onset mood syndrome (major depressive or bipolar, 
anxiety symptoms, or psychosis during the study period or screening phase) patients will be immediately 
offered such treatment. Subjects will be ineligible for study participation if they meet any exclusion criteria 
as a result of such clinical developments. Since POMA is an experimental medication, it will not be 
available to subjects at the end of the trial.
 
Patients in this study will continue their usual treatment with their usual psychiatrist and clinician without 
interruption or changes. There is currently no standard best clinical practice (psychotherapeutic or 
psychopharmacologic) for prodromal stages of psychotic disease. Available antipsychotic therapies have 
been studied and are associated with improved prodromal symptoms and lessening of transition to 
psychosis, but are associated with a significant side-effect burden, including EPS, weight gain, and 
hyperlipidemia, amongst other side effects. The evidence for efficacy of cognitive-behavioral interventions 
for prevention of transition to psychosis is also mixed to date.
Risks/Discomforts/Inconveniences 
Risks that could be encountered during the study period
1) Risks and Discomforts Associated with LY2140023 (Pomaglumetd, “POMA”) Administration 
Approximately 582 healthy subjects and 2877 subjects/patients with schizophrenia have been 
exposed to POMA in prior studies.  Across groups, nausea, vomiting, increased heart rate, and 
eosinophilia as assessed by laboratory values were commonly reported (≥1% and <10%) in 
patients treated with POMA.
Healthy controls: 582 healthy control subjects received doses ranging from an acute dose of 
5mg to 200 bid for up to 14 days. Most of the adverse events reported were mild, and the subjects 
recovered without sequelae. The most common AEs (≥10%) in clinical pharmacology studies 
conducted in healthy subjects were: nausea, headache, vomiting, and dizziness. The following 
SAEs have been reported in healthy subjects: infected sebaceous cyst (1), deep vein thrombosis 
(1), pulmonary embolism (2), and syncope due to vasovagal event (1). With the exception of 
syncope due to vasovagal event, none of these SAEs were reported by the investigator as related 
to administration of POMA.
Most pertinent to the proposed dose in this study, multiple doses of POMA, administered 
up to 160 mg BID, were well tolerated in the healthy subject population, including 5 healthy 
controls receiving 160 mg BID (greater or equal 320 mg per day) for 14 days and 2 receiving 200 


Protocol Summary Form
7459
Small, Scott
Page 18 of 27
mg bid without significant side effects. There were no serious adverse events and all subjects 
completed. The most commonly reported adverse events were headache, nausea, epistaxis, 
diarrhea, dizziness, somnolence, tremor, pruritus and feeling hot. The profile of drug-related 
adverse events were similar to those reported in previous clinical pharmacology studies in healthy 
volunteers, and those reported in clinical studies with patient populations. There were no dose 
limiting events observed in doses up to 160 mg BID. The study was terminated prematurely by the 
Sponsor in response to two cases of convulsions observed in an ongoing Phase 2 study in 
schizophrenia patients, involving dose levels lower than doses administered in this study. 
Although no serious adverse events occurred the healthy control dose escalation study, the 
decision was taken to stop the study whilst the 200 mg dose level was ongoing
There were generally no clinically significant values, changes, or trends in clinical 
laboratory data or vital signs. An increased esoinophil count was observed after 15 days of dosing 
with 40 mg POMA. However, similar eosinophil changes were not seen at higher dose levels, so 
there is no apparent dose dependency of the change. In addition, there were no concomitant 
cutaneous reactions associated with the eosinophil changes, so the clinical significance remains 
unclear. There were no clinically significant changes in ECGs which is consistent with findings, 
suggesting that doses of POMA up to 160 mg BID are not associated with QTc prolongation. This 
study incorporated EEG measurements to explore potential prodromal signs of convulsions at 
higher than previously administered doses of POMA. The results of the EEG measurements in 
this study showed that there was no abnormal EEG activity associated with POMA, administered 
up to 160 mg BID. 
Patient populations:  Table 6.4 from the IB (attached) provides a summary of TEAEs for patients 
who were assigned to take either placebo or POMA in completed studies.  In the placebo-
controlled studies, 727 patients were assigned to placebo, and 1555 were assigned to POMA . 
There was not a significant difference in adverse events when comparing patients taking placebo 
with patients taking POMA , 403 (55.4%) and 901 (57.9%), respectively. The common adverse 
events reported in ≥2% of patients treated with POMA were: schizophrenia (underlying disease-
related events), eosinophilia, anxiety, acute extrapyramidal symptoms, vomiting, abdominal pain, 
insomnia, headache, nausea, anxiety, blood CPK increased, agitation, constipation, abdominal 
pain, and dyspepsia. Nausea was significantly higher in the POMA pooled group compared with 
the placebo group (6.8% vs. 4.1%, p=.005), as were vomiting (4.1% vs. 2.5%, p=.032) and 
eosinophilia (4.8% vs. 1.0%, p=.003). 
The most common TEAEs reported in ≥2% of patients assigned to POMA in 1 or more of 
the completed long-term safety studies were: schizophrenia-related events, nausea, insomnia, 
headache, vomiting, nasopharyngitis, blood CPK increased, anxiety, decreased appetite, diarrhea, 
dizziness, tremor, fatigue, weight decreased, nasopharyngitis, upper respiratory tract infection, 
agitation, dyspepsia, bronchitis, back pain, cough, depression, restlessness, abdominal 
discomfort, blood pressure increased, constipation, rash, tooth ache, arthralgia, back pain, 
somnolence, akathisia, dry mouth, irritability, pruritus, and upper abdominal pain. 
In the placebo-controlled studies there was a statistically higher incidence of abnormally 
high eosinophils at any time in the pooled POMA group compared with placebo (POMA 5.5%; 


Protocol Summary Form
7459
Small, Scott
Page 19 of 27
placebo 0.9%; p<.001). There was also a statistically significant mean increase in eosinophils 
during administration of POMA administration when compared to baseline or placebo. 
The significance of the eosinophila is unknown but there have been no clear clinical 
correlates to the eosinophil elevations. There have been no other consistent or clinically significant 
changes in laboratory values in the placebo-controlled studies.
In other studies, people who took compounds similar to POMA have experienced rash, skin 
itching, or skin peeling. Because of these experiences, rash, itching of the skin or skin peeling will 
be closely monitored. Subjects will be asked at every visit about these skin conditions.
Most pertinent to the present project, 44 patients with schizophrenia completed a multiple dose 
escalation study over a dose range of 160 to 480 mg BID for 7 days. The tolerability of POMA 
dosing was improved after the first day of dosing. In general, the TEAEs of nausea and vomiting 
occurred more frequently on first exposure to POMA. There was no apparent trend in the severity 
of TEAEs with increasing dose. The MTD for was not reached in this multiple ascending dose 
study. There were no clinically meaningful changes in ECG parameters and no positive correlation 
between plasma concentrations of POMA and changes from baseline in QTc across all the doses. 
A dose of 400 mg, which was approximately 5 times the anticipated clinical dose, did not prolong 
QTcF to a clinically significant degree.
Deaths: There were 18 deaths reported in completed studies (out of over 3000 human 
exposures). In these 18 death cases, 12 patients were assigned to take POMA, 3 patients were 
assigned to take placebo, 1 patient was assigned to take olanzapine, and 2 patients did not take 
any study drug. Also, of these 18 death cases, 7 were completed suicides with 5 of those patients 
assigned to take POMA. Of the 12 patients assigned to take POMA, 5 of those deaths occurred 
after the study drug had been held or discontinued. Also, of the 12 patients assigned to take 
POMA, 9 of those deaths were considered to be not related to the study drug treatment by the 
investigator, while all 12 deaths were considered to be not related to the study drug treatment by 
the sponsor. A listing of death cases for completed studies is presented in Table 6.1 in the IB 
(attached).
SAE: Overall, there were 361 case reports of SAEs (excluding the 18 deaths in patients) in POMA 
clinical trials. In the placebo-controlled studies, 727 patients were assigned to placebo, and 1555 
were assigned to POMA. There was not a significant difference in SAEs when comparing patients 
taking placebo with patients assigned to POMA, 25 (3.4%) and 43 (2.8%), respectively. The only 
SAE reported ≥1% patients was schizophrenia-related, with no statistically significant differences 
observed when comparing patients taking placebo with patients taking POMA. 
Overdose: The effect of a single dose of activated charcoal on the PK of POMA and LY404039 
was examined in healthy subjects. Activated charcoal reduced the area under the curve from time 
zero to infinity (AUC0-∞) and Cmax of both POMA  and LY404039 by approximately 25% and 
35%, respectively, when administered 1 hour after a single 80-mg dose of POMA . However, the 
median time to maximum concentration (tmax) of neither analyte was affected by administration of 
activated charcoal. 


Protocol Summary Form
7459
Small, Scott
Page 20 of 27
Signs and Symptoms: There is limited information on signs or symptoms of POMA overdose or on 
treatment of overdose in humans. In clinical trials, 1 case of ingesting approximately 1800 mg of 
POMA in combination with lorazepam was reported. The patient did not experience any significant 
medical consequences of the overdose and spontaneously recovered without medical 
intervention. 
Management of Overdose: No specific antidote is known. Symptomatic treatment and monitoring 
of vital organ function according to clinical presentation is recommended.
Risk of Serotonin Syndrome
 
POMA increases levels of serotonergic metabolites in humans (Lowe et al., 2012) and therefore there is a 
theoretical increased risk of serotonin syndrome when POMA is administered with a serotonergic 
medication, such as an antidepressant. There is insufficient experience in humans to know whether this risk 
of more than theoretical. However, in order to protect against this risk, we will review serotonin syndrome 
as part of the standard consent process with all patients, include a full paragraph in risks section of the 
consent form discussing this theoretical risk, and review side effects at every visit, as previously described. 
In addition, we are already excluding individuals with any severe medical condition or history of seizure 
disorder, and have implemented a robust schedule for adverse event monitoring, including safety labs and 
medical/physical examination.
 
Seizure Risk
 
In all of the studies performed with POMA in human subjects, events of seizure were reported in 6 patients 
treated with POMA at 5, 20, and 80 mg BID. Additionally, seizures were reported in 1 patient randomized 
to risperidone and 1 patient during a placebo-lead in period. Seizures were reported in an additional 3 
patients prior to them being randomized to study medication. There was 1 additional report of convulsion 
that was determined not to be seizures.
Specific Vulnerabilities 
There are no known specific vulnerabilities for a CHR (clinical high risk) population. However, we will 
obtain an independent assessment of capacity for all subjects, and will also perform the SIPS and CGI and 
GAF weekly while in the study to follow clinical status.
 
Risks and Discomforts Associated with Compound LY404039 in Humans
A breakdown product of POMA, called LY404039, has been given to 24 healthy people in a 
previous study. Experiences reported by 2 or more people who have taken LY404039 were 
headache, feeling dizzy upon standing up, stomach pain, nausea (feeling sick to the stomach), 
sore throat, tiredness, or feeling sleepy. 
Risks and Discomforts Associated with LY2140023 (Pomaglumetad, “POMA”) in Animals
POMA has been studied in animals. Rats treated with POMA showed uncoordinated movement, 
problems with walking, reduced body weight, uncontrollable and rapid shaking (convulsions or 


Protocol Summary Form
7459
Small, Scott
Page 21 of 27
possible seizures), or death. In 1 out of 40 rats treated with very high doses of POMA for 6 
months, areas of brain injury were observed. Mice treated with POMA also showed uncontrollable 
and rapid shaking (convulsions or possible seizures). Vomiting, soft or watery stools, and/or a 
severe rash were seen in monkeys given high doses of POMA for up to 1 year. A single monkey 
was euthanized due to severe skin rash on Day 235 of the 1-year study. No convulsions have 
been observed in monkeys. In a study of the effects of POMA on pregnant rats and their offspring, 
some baby rats had significant decreases in their body weight, and some baby rats died up to 14 
days after birth. The levels of drug in subject’s blood will be lower than the levels of drug in 
monkeys at which the above bad effects were noted. Effects of convulsion observed in rats and 
mice were observed at blood drug levels that are similar to or lower than the levels expected in 
this study.
Summary
 
Doses of POMA as high or higher than the highest dose in this study (160 mg twice a day) have been taken 
by 24 healthy people without psychiatric illness for 10 days in a previous study without significant side 
effects. 44 patients with schizophrenia completed a multiple dose escalation study over a dose range of 160 
to 480 mg BID for 7 days. Therefore, this dose and higher has been given before, but not for this length of 
time (14 days, though 7 and 10 days have been given).
 
 
2) Interviews and ratings (general): Study participants may feel anxious during medical history interviews or 
during administration of specific rating scales.
 
3) Brain imaging scans (general): It may be uncomfortable to lie motionless in the MRI scanner and it may 
cause some subjects to feel anxious.
 
4) Intravenous catheter: Intra-venous lines can cause pain, bleeding, or occlusion/clotting.
 
5) MRI Imaging: The Magnetic Resonance (MR) scanner uses strong magnetic fields and radio waves to 
take measurements in the brain. MRI involves lying on a table that slides into a large magnet shaped like a 
cylinder. Before beginning the procedure, we will determine that patients do not have a pacemaker or any 
unsafe metallic implants such as an aneurysm clip or heart valve and certain tattoos, and they will be asked 
to remove any metal or magnetized objects (such as keys, chains, jewelry, retainers, medication patches, 
hairpins or credit cards). In addition, they will complete a brief interview at the time of study inclusion to 
determine if they have Asthma or a history of renal failure that may exclude their ability to receive an 
injection of Gadolinium (see below section). These questions will be repeated on the day of the scan.
 
For the scanning procedure, they will be asked to lie flat on the back in the MRI scanner for approximately 
60 minutes and to remain as still as possible. Some people have reported sensations during MRI scans, such 
as "tingling" or "twitching" (or, very rarely, a painful sensation), which are caused by changes in the 
magnetic field that can stimulate nerves in the body. With any MRI scan, on occasion, some people 
experience nervousness or discomfort due to the scanner's small space and the need to lie still. Except for 


Protocol Summary Form
7459
Small, Scott
Page 22 of 27
pacemakers, some types of metallic implants, and medication patches, we are not aware of any other 
potentially dangerous interactions or hazards associated with the MRI scan. The MRI scanner also produces 
a loud noise.
6) Gadolinium compounds do have side effects, we use Dotarem. One side effect of gadolinium is nausea 
and vomiting, observed in less than 2 people out of every 100 injected. (1.8% estimate). Dry mouth (less 
than 2%), dizziness (0.7% up to 3.6%), and headache (2.2% up to 5.8%) are infrequent, yet possible side-
effects. An additional side effect is hives, observed in less than 1 person out of every 100 injected with 
gadolinium. All of these side effects resolve within 20 minutes to several hours. People with asthma or 
known sensitivities to contrast agents are at increased risk for more serious side rare side effects (less than 
1/10,000 injections estimate), such as severe allergic reaction that may result in sudden
difficulty breathing, and therefore will not be injected with Gadolinium.  Some patients with acute renal 
failure or end-stage renal disease have developed a serious medical condition known as nephrogenic 
systemic fibrosis (NSF) after the use of gadolinium for MRI. The primary concern regarding risks to renal 
function from gadolinium-based contrast agents (GBCAs) is specific to this population of patients who have 
end-stage renal disease (ESRD) on hemodialysis, or acute, florid, clinical renal failure, and then are exposed 
to gadolinium. This population of patients is by definition excluded from this study by virtue of medical 
history and general review of systems. Renal dysfunction as a result of gadolinium in a population without 
history of end-stage renal disease or acute renal failure has not been described in the medical literature. In a 
retrospective study conducted at two large medical centers, 74,124 patients were
injected with a standard dose of gadolinium (0.1mmol/kg, the same dose used in our research studies) who 
had no screening for renal function, with a rate of zero/74,124 cases of renal complications (e.g., 
nephrogenic systemic fibrosis (NSF) or other renal dysfunction) post injection (Prince, Zhang et al. 2008). 
All 15 cases of NSF that were found in this retrospective study all had severe, clinical renal failure at the 
time of gadolinium injection. No cases of NSF have been identified in persons with normal renal function or 
with moderate renal dysfunction.
 
Regarding this specific risk, the FDA recommends:
1. Become familiar with the patient populations at risk for NSF.
2. Avoid using gadolinium in patients with known risks for developing NSF.
3. Prior to administering gadolinium, evaluate patients for renal dysfunction by assessing their renal 
function, either by obtaining a medical history or conducting laboratory tests that measure renal function.
4. When administering gadolinium, do not exceed the recommended dose in product labeling and allow a 
sufficient period of time for elimination of the agent from the body prior to any further gadolinium
administration. The American College of Radiology recommends, as of July 2007, pre-screening patients 
prior to the administration of Gadolinium-Based MR Contrast Agents (GBMCA) their glomerular filtration
rate (GFR) for the following patient groups:
1. Renal disease (including solitary kidney, renal transplant, renal tumor)
2. Age >60
3. History of Hypertension
4. History of Diabetes
5. History of severe hepatic disease/liver transplant/pending liver transplant. For patients in this category 
only, it is recommended that the patient's GFR assessment be nearly contemporaneous with the MR 
examination for which the GBMCA is to be administered. Concurrently, researchers investigating clinical 


Protocol Summary Form
7459
Small, Scott
Page 23 of 27
risk factors as well as the role of gadolinium formulation in development of NSF (Peak and Sheller 2007; 
Kanal, Broome et al. 2008) note that the Gadolinium-based contrast agents may possess differential risk of 
NSF depending upon their chemical structure. Gadolinium agents are classified on the basis of chelate 
biochemical structures (macrocyclic vs linear) and chelate charge (ionic vs nonionic) (Perazella 2007). 
Macrocyclic molecules bind gadolinium more tightly than do linear chelates, possess high thermodynamic 
conditional stability, and have lower dissociation rates. Ionic cyclic chelates are
thought to be the least likely to release free gadolinium, whereas nonionic linear chelates are the most likely 
to release free gadolinium in the body. Risk of NSF is considered to be the highest with Omniscan and 
OptiMARK, which carry no molecular charge, are arranged in a linear structure with excess chelate, and 
seem more likely to release free gadolinium into the body. Since gadodiamide (Omniscan) has been most 
commonly associated with NSF(Thomsen 2006) and gadopentetate dimeglumine (magnevist) second-most 
associated ; the Neurological Institute’s imaging center has changed contrast agents from Omniscan to 
Dotarem, a macrocyclic ionic agent.
 
The dosing guidelines for the brand of gadolinium to be used in this study are as follows: CNS (Central 
Nervous System) Adults: The recommended dose of Dotarem 0.1mmol/kg (0.2 mL/kg) administered as a 
rapid bolus intravenous injection. According to the Multihance package insert and the recent literature, 
repeated dosing of mutihance up to a total dose of .3mmol/kg (in three doses of 0.1mmol/kg) can be 
immediate given within a short time-span with no adverse effects. The elimination half-life of the compound 
is 1-2 hours. Prior to readministration, the FDA recommends 'sufficient time for drug elimination'. Our 
study design of a single baseline dose at 0.1mmol/kg followed by repeated injection 2 weeks later is more 
than adequate time for elimination of contrast agent, which should be complete by two days, and is well 
below the maximal dosing guidelines that have been shown to be safe with repeated dosing in prior studies.
 
COVID Risks There is a risk of exposure to COVID when deciding to go out in public and travel for 
research.
 
Describe procedures for minimizing risks
1) POMA: In order to minimize risk, we will exclude any individual with any history of seizure disorder, or 
any severe medical condition. We will obtain frequent laboratory analyses, including liver
tests, and cbc, adverse event queries, and EKGs and temperature during this study. Patients will be 
terminated from the study if they develop side effects that are, in the opinion of the PI, preclusive of 
continuing in this protocol or in particular if they meet worsening criteria based on the CGI or need for prn 
medications.
 
2) Interviews and ratings (general) Participants will be allowed to take breaks as necessary and are not 
required to answer any questions that may be uncomfortable.
 
3) Brain imaging scans (general): Our staff will be available to provide support, reduce anxiety, optimize the 
comfort of the subject and remove the subject from the MRI magnet bore if requested.
 
4) Intravenous catheter: Placement risks are minimized by using proper techniques.


Protocol Summary Form
7459
Small, Scott
Page 24 of 27
 
5) MRI Imaging: Before beginning the procedure, we will determine that patients do not have a pacemaker 
or any unsafe metallic implants such as an aneurysm clip or heart valve and certain tattoos, and they will be 
asked to remove any metal or magnetized objects (such as keys, chains, jewelry, retainers, medication 
patches, hairpins or credit cards). In addition, they will complete a brief interview at the time of study 
inclusion to determine if they have Asthma or a history of renal failure that may exclude their ability to 
receive an injection of Gadolinium (see below section). These questions will be repeated on the day of the 
scan. The MRI scanner also produces a loud noise; earplugs will be provided to reduce this discomfort. If a 
patient experience any discomfort and wish to stop the scan, he/she can tell the MRI technologist who will 
stop the scan immediately. In our experience, no one has had sensations from the MRI that did not stop 
when the scanning stopped.
 
6) Gadolinium -A trained physician will inject the gadolinium and remain with the patient for the entire 
duration and for 15minutes after the scanning session is complete. Prior to scan, all participants being 
considered for participation in this study will continue to have a complete medical history prior to MRI to 
screen for renal failure/history of renal disease, diabetes, or hypertension, as well as screening labs. Patients 
with a diagnosis of acute renal failure are invariably severely medically ill and hospitalized, and are not 
eligible for study participation. In the current protocol, we administer Dotarem according to the patient's 
weight at a dose of 0.1mmol/kg. Based upon the amount administered, we do not exceed the recommended 
dosage. In addition, an Epi Pen will be available at all times during scanning with gadolinium. 
 
COVID Risks: We will instruct subjects to wear a mask in public and while traveling, practice hand 
hygiene, and stay at least 6 feet away from others. We will tell subjects that if they do not feel 
comfortable traveling to the medical center for an appointment, for example if the subway or bus they 
would normally take is crowded, they can reschedule, or we may be able to arrange alternative 
transportation (if it is the case that alternative transportation, such as Uber or Lyft, can be offered). 
We have also minimized in-office visits to lessen this risk. We will keep our subjects informed about 
current public health recommendations, such as federal and local government guidelines and 
directives.
 
Methods to Protect Confidentiality
Describe methods to protect confidentiality
All records of the participating subjects will be kept in a locked room with access provided only to staff 
members. All data collected will be kept confidential and used for professional purposes only. Publications 
using these data will be done with only deidentified data. As this study is an intervention study utilizing an 
IND there is a possibility that the FDA will inspect our records.
 
When done remotely, we will use redcap to obtain consent on the cfs and hipaa forms. When sending 
electronic messages to subjects, we will only use encrypted email (NYSPI encrypted) and when 


Protocol Summary Form
7459
Small, Scott
Page 25 of 27
sending attachments with PHI only use the NYSPI secure file transfer website 
(https://attach.nyspi.org/) or encrypted nyspi email or redcap.
When COPE staff work from home, we all use the nyspi onedrive sharepoint system for storing 
documents or HIPAA compliant storage devices for paper documents. When conducting remote 
visits, we will use telephone or hipaa compliant video conferencing.
 
Will the study be conducted under a certificate of confidentiality?
Yes, we have already received a Certificate of Confidentiality
Direct Benefits to Subjects  
Direct Benefits to Subjects
There are no direct benefits for participating patients.
Compensation and/or Reimbursement 
Will compensation or reimbursement for expenses be offered to subjects?
Yes
Please describe and indicate total amount and schedule of payment(s). 
Include justification for compensation amounts and indicate if there are bonus payments.
Subjects will receive $50 per visit, not including MRI, up to 5 total visits (up to 3 for screening, day 7, day 
14). In addition, patients will receive $150 for participation in each MRI imaging with gadolinium contrast 
(up to 2). Subjects will also receive reimbursement for local transportation. Payments will be made in cash 
or check. The total estimated compensation for this study is approximately $550.
 
For the test retest study, healthy subjects will receive $50 for their screening visit, not including MRI, 
and $100 for participation in each MRI imaging with gadolinium contrast (up to 4). Subjects will also 
receive reimbursement for local transportation. Payments will be made in cash or check. The total 
estimated compensation for this study is approximately $450. 
References
References
First, M.B., Spitzer RL, Gibbon M, and Williams JBW. Structured Clinical Interview for DSM-IV Axis I  
Disorders, Clinician Version (SCID-CV). (American Psychiatric Press, Inc., Washington D.C., 1996). 


Protocol Summary Form
7459
Small, Scott
Page 26 of 27
Guy, W. Clinical Global Impressions. in ECDEU Assessment Manual for Psychopharmacology:
Revised, ADM 76-338 (ed. Guy, W.) 217-222 (Department of Health, Education, and Welfare,
Washington, DC, 1976).
 
Hollingshead, A.B. Four-Factor Index of Social Status, (Yale University, Department of Sociology, New
Haven, CT., 1975).
 
Levine, J. & Schooler, N.R. SAFTEE: a technique for the systematic assessment of side effects in
clinical trials. Psychopharmacol Bull 22, 343-381 (1986).
 
Lowe S, Dean R, Ackermann B, Jackson K, Natanegara F, Anderson S, Eckstein J, Yuen E, Ayan-
Oshodi M, Ho M, McKinzie D, Perry K, Svensson K. Effects of a novel mGlu₂/₃ receptor agonist 
prodrug, LY2140023 monohydrate, on central monoamine turnover as determined in human and rat 
cerebrospinal fluid. Psychopharmacology (Berl). 2012 Feb;219(4):959-70.
 
Marder, S.R. & Fenton, W. Measurement and Treatment Research to Improve Cognition in
Schizophrenia: NIMH MATRICS initiative to support the development of agents for improving cognition
in schizophrenia. Schizophr Res 72, 5-9 (2004).
 
Miller, T.J., et al. Prospective diagnosis of the prodrome for schizophrenia: Preliminary evidence of
interrater reliability and predictive validity using operational criteria and a structured interview. Am J
Psychiat 159, 863-865 (2002).
 
Niendam, T.A., Bearden, C.E., Johnson, J.K. & Cannon, T.D. Global Functioning: Role Scale,
(University of California, Los Angeles, Los Angeles, CA, 2006).
 
Auther, A.M., Smith, C.W. & Cornblatt, B.A. Global Functioning: Social Scale, (Zucker Hillside Hospital, 
Glen Oaks, NY, 2006).
 
Oquendo, M.A. & Mann, J. Risk Factors for suicidal behaviour: utility and limitations of research
instruments. in Standardized Evaluation in Clinical Practice. (ed. First, M.B.) 103-130 (2003).
 
Revheim, N. & Medalia, A. The independent living scales as a measure of functional outcome for
schizophrenia. Psychiatr Serv 55, 1052-1054 (2004).
 
Schobel SA, Chaudhury NH, Khan UA, Paniagua B, Styner MA, Asllani I, Inbar BP, Corcoran CM, 
Lieberman JA, Moore H, Small SA. Imaging patients with psychosis and a mouse model establishes a 
spreading pattern of hippocampal dysfunction and implicates glutamate as a driver. Neuron. 2013 Apr 
10;78(1):81-93.
 
Simpson, G.M. & Angus, J.W.S. A rating scale for extrapyramidal side effects. Acta Psych Scand
212(suppl.), 11-19 (1970).


Protocol Summary Form
7459
Small, Scott
Page 27 of 27
Small SA. Isolating pathogenic mechanisms embedded within the hippocampal circuit through regional 
vulnerability. Neuron. 2014 Oct 1;84(1):32-9.
 
Uploads
Upload the entire grant application(s)
Upload copy(ies) of unbolded Consent Form(s)
Consent Form(081320)Bolded.pdf
Consent Form(081320)unBolded.pdf
Upload copy(ies) of bolded Consent Form(s)
Upload copy(ies) of unbolded Information Sheet(s)
Upload copy(ies) of bolded Information Sheet(s)
Upload evidence of FDA IND approval(s)
Upload a copy of Certificate of Confidentiality
Upload copy(ies) of the HIPAA form
Upload any additional documents that may be related to this study

SAP_001.pdf: 
COVER PAGE 
 
STATISTICAL ANALYSIS PLAN 
 
OFFICIAL TITLE: Glutamate Reducing Interventions in Schizophrenia 
 
NCT NUMBER: NCT03321617 
 
 
 
DATE OF DOCUMENT: September 2, 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis 
 
Sample size and randomization: For the sample (n=3 subjects per 4 doses) the randomization 
sequences will be balanced in blocks of 4. 
 
Primary outcome: Change (hypothesized decrease) in left CA1 CBV from baseline to 14 days. 
Adherence, dropouts, and missing data: As this is a dose finding trial it is highly important that 
analyses be done on subjects who adhere closely to taking the study drug across the 14 days 
and who have complete data. We have set a threshold of adherence at >80% compliance. 
Subjects who are non-adherent, dropout, or who have unusable CA1 values at baseline or 14 
days will be replaced. 
 
Hypothesis testing (Go No-Go Criteria): The hypothesis to be tested is that at least one of the 4 
doses shows a mean decrease in left CA1 CBV from baseline to 14 days of at least 0.33 standard 
deviations. Given that this is a dose finding study, to confirm the hypothesis we will not require 
a statistically significant test (e.g. p<.05), but instead will require the estimated mean decrease 
across the 3 patients in any one dose to be at least 0.33 standard deviations (standardized 
change will be used as the effect size measure). One-way ANOVA of the change scores on the 4 
dose levels will be used to estimate the mean changes for each dose level standardized by the 
pooled standard deviation of change. Based on our prior data, the test-retest reliability of CA1 
CBV (taken across 3 weeks in 4 patients on placebo) is very high (ICC = 0.85) providing 
confidence in the specificity of our measure of change and justification for including 3 patients 
at each level. 
 
The target mean decrease of 0.33 standard deviations was chosen based on: 1) it represents 
half of the difference found between healthy controls and CHR patients in previous work and 2) 
we expect any decrease in CA1 CBV to be related to improvement in symptoms given our 
finding of a linear relationship between CA1 CBV and symptoms in CHR. 
 
Similar analyses will be conducted for our secondary measures of hippocampal Glx (MRS). The 
clinical symptoms (SIPS) and cognitive measures (Matrics) are measured at 7 and 14 days and 
will be modeled with repeated measures ANOVA summarizing average change by dose over the 
study period. The safety measures (e.g. side effects) will be measured similarly throughout the 
study and will similarly be modeled with repeated measures ANOVA providing estimates at 
each time point and also aggregated across the study.