Clinical trial NCT02034474
Conditions: Schizophrenia Schizoaffective Disorder
Sponsor: New York State Psychiatric Institute
Start date: 2014-02-01; Completion date: 2017-02-06
Enrollment: 59 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Randomized, double-blind clinical trial of tocilizumab vs. placebo as add-on treatment for residual positive, negative, and cognitive symptoms in schizophrenia. The primary study hypothesis is that individuals receiving tocilizumab will show greater improvements in their PANSS total scores than those taking placebo.

Detailed description:
One of the main mediators of the effects of infection/inflammation in the human body is cytokines. Recent data suggest that cytokines, and in particular IL-6, may mediate the effects of lifetime or prenatal infection on schizophrenia risk. Preclinical models of schizophrenia support a convergence between a role for IL-6 in the pathophysiology of schizophrenia and the major neurochemical hypotheses of schizophrenia-the dopamine and glutamate hypotheses. Namely, IL-6 dysfunction or excess promotes schizophrenia-like behaviors and schizophrenia-like biochemical and electrophysiological profiles, while IL-6 knockout or neutralization mitigates these abnormalities. Furthermore, plasma IL-6 levels are elevated in acutely psychotic but not treated patients, and Positron Emission Tomography (PET) studies have shown active inflammation in the brains of individuals with psychosis. Finally, treatment of individuals with schizophrenia with non-specific anti-inflammatory agents, such as celecoxib and aspirin, has suggested a role for anti-inflammatory agents in schizophrenia. These data also suggest that studies of immunologic agents that more specifically target the underlying pathophysiology of schizophrenia may be more efficacious. Tocilizumab (Actemra®) is an FDA-approved humanized monoclonal antibody against the IL-6 receptor used for treatment of rheumatoid arthritis in individuals who have not responded to at least one TNF-alpha therapy and for juvenile idiopathic arthritis

Arms: arm 1: Tocilizumab will be administered at day 0, week 4 and week 8 via an iv drip over 60 min. Dose is 8mg/kg but may be reduced to 4mg/kg if intolerable. Maximum dose will be 800mg. arm 2: Placebo will be administered intravenously via an iv drip over 60 min
Interventions: intervention 1: Tocilizumab intervention 2: Placebo
Intervention descriptions: intervention 1: 8mg/kg intravenously via iv drip over 60 min intervention 2: intravenously via iv drip over 60 min

Protocol documents:
SAP_002.pdf: 
 
 
COVER PAGE 
 
STATISTICAL ANALYSIS PLAN 
 
OFFICIAL TITLE: Tocilizumab as Add-On Treatment for Residual Positive, 
Negative, and Cognitive Symptoms of Schizophrenia: A Randomized, Double-
Blind, Placebo-Controlled Clinical Trial 
 
NCT NUMBER:  NCT02034474 
 
DATE OF DOCUMENT: May 20, 2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
 
Primary analysis will be conducted between the placebo group and the tocilizumab group, and the primary outcome 
will be the PANSS Total scores.  This measure has been well-validated in prior clinical studies and is expected to 
show standard normal distribution, although this will be verified prior to data analysis.  Comparisons on other 
behavioral, cognitive, functional, and biochemical measures will be secondary outcomes.  All subjects who have 
participated in a post-randomization rating will be included in the analysis.  
As an initial analysis, we will investigate group differences in PANSS Total scores by using a two-group t test, 
comparing the mean change across the treatment period (i.e., mean change at 4 week, 8 week, and 12 week time 
points). If this analysis suggests an effect, we will perform repeated measures analyses (ANOVA) to assess for 
effects of time (i.e., group by repeated measure interaction) on the primary outcome. p values will be set at 0.05.  
Anti-cholinergic agents will be considered covariates in our cognitive analyses.  Pearson product moment or 
spearman rho correlations, depending on observed distributional properties, will be performed on change scores to 
determine interrelationships in improvement between clinical/cognitive measures, cytokine levels, and tocilizumab 
doses.  If there are major biases within or between treatment groups, effort will be made to assess the impact on 
results (99).   
Sample size calculations are conservatively based upon expectation of a moderate effect-size improvement (d=0.6) 
in the PANSS total score in tocilizumab group compared to placebo group. Based upon a sample size of 45 in the 
tocilizumab group and 45 in the placebo group, the study will have power of 0.8 to detect a moderate effect size 
(d=0.6, with α < 0.05) for treatment related change in the PANSS total score for the tocilizumab group compared to 
the placebo group.  Other measures are experimental, so power to detect change cannot be computed.  Nevertheless, 
pilot data of this type is essential for establishing feasibility of these interventions, determining effect sizes and 
competing successfully for large scale funding. 
 

ICF_001.pdf: 
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 “Tocilizumab, An Il-6 Receptor Antibody, As Add-On Treatment For Residual Positive, 
Negative, And Cognitive Symptoms Of Schizophrenia: A Randomized, Double-Blind, Placebo-
Controlled Clinical Trial” 
Consent summary form 
 
Below is a summary of the study you are being asked to participate in.  This outline is meant to 
be a guide for you to use while considering the study and reading the consent form. It is not meant to 
replace the consent form you will need to sign if you decide to participate in the study.  The consent 
form contains much more detailed information about the study and the risks you will need to consider 
in order to make your decision. 
• You are asked to participate in research study that looks at how a drug, tocilizumab, affects the 
symptoms of schizophrenia. 
• It is important that you understand that you will receive no personal benefit from your 
involvement in the research itself. 
• You will participate in several psychological tests that examine your symptoms of 
schizophrenia. 
• This research study may be completed as an inpatient or an outpatient and will take 
approximately 16 weeks 
• Tocilizumab is given as an intravenous (IV) medication, which means that you will need an IV 
each time you get it, up to three times. 
• You will have the option of doing up to two magnetic resonance imaging (MRI) brain scans 
with dye. You do not need to do any MRI scans to participate in the research study of 
tocilizumab-the MRI part is optional. Each scan takes about one hour to complete. One scan is 
done at the beginning of the study and one at the end of the study. 
 
Risks of tocilizumab drug: 
• Tocilizumab is an FDA-approved medication for rheumatoid arthritis and juvenile idiopathic 
arthritis. 
• Some possible side effects include chills, nausea, vomiting, a severe allergic reaction, 
nasopharyngitis, high blood pressure, rash, abdominal pain, diarrhea, mildly elevated liver 
blood tests, headache, dizziness, elevated cholesterol levels, or worsening of symptoms.  You 
will be constantly watched during the drug administration to ensure your health and safety.  We 
will stop giving the drug if there are any safety concerns. 
• You will be given an 8mg/kg dose of tocilizumab, or a placebo. 
• If you decided to do the MRI part of the study, there are additional possible side effects and 
potential risks you should know about, and these are detailed in the consent form. For example, 
there is a dye used in the MRI, gadolinium, which may have side effects, including nausea, dry 
mouth, dizziness, headache, hives, and a rare kidney condition called nephrogenic systemic 
fibrosis. The details of the common and rare side effects of this dye are listed in the consent 
form and you can discuss these with the study doctor.  
 
As in all research, it is your choice to participate in this study and you do not have to participate if you 
do not want to. Also, you may stop participating at any time.  This research study is not meant to 
benefit you directly. Please read the Consent Form carefully and ask the study physician any questions 
or concerns you might have. 


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NEW YORK STATE PSYCHIATRIC INSTUTUTE 
COLUMBIA UNIVERSITY DEPARTMENT OF PSYCHIATRY 
CLINICAL INVESTIGATION CONSENT FORM 
 
(For patients participating in “Tocilizumab, An Il-6 Receptor Antibody, As Add-On 
Treatment For Residual Positive, Negative, And Cognitive Symptoms Of 
Schizophrenia: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial”) 
 
Purpose of Study 
You are being asked to participate in a research study of tocilizumab.  You 
qualify to participate in this study because you are between 18 and 59 years old and have 
a diagnosis of schizophrenia or schizoaffective disorder. This study is paid for by the 
Stanley Medical Research Institute. The study drug, tocilizumab, is being provided by the 
makers of tocilizumab, Genentech. 
 
For this study you will receive a drug called tocilizumab, or placebo, which is 
saline water and does not have any tocilizumab in it. The drug or placebo will be given 
into a vein in your arm over 60 minutes. You will not know whether you will receive 
tocilizumab or placebo. Tocilizumab is drug that is FDA-approved for rheumatoid 
arthritis and juvenile idiopathic arthritis. The main purpose of this study is to see if it 
affects your symptoms of schizophrenia. It has never been studied in a clinical trial of 
people with schizophrenia. In order to examine your symptoms of schizophrenia, you will 
take several psychological tests. If you have already participated in the general 
schizophrenia research study at the New York State Psychiatric Institute, you may have 
already finished some of this testing. If so, we will use the results of those tests for this 
study. If you have not taken these psychological tests before, you will take them as part 
of your participation in this study. 
 
You will also have the option of doing an MRI scan at the beginning and end of 
the study. The MRI scans are optional-you do not need to do the MRI scans to do the 
study of tocilizumab. 
 
Alternatives to study participation 
This is not a treatment study: data are being collected for research purposes only. The 
alternative would be to not participate in this research study and to continue with your 
treatment as usual, which may include medications, therapy, and other interventions. 
Medications such as tocilizumab are available for use but have not yet been studied in 
individuals with schizophrenia.  It is also 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.   
 
Study Procedures 
Participation in the general schizophrenia research study and evaluation 
If you are interested in participating in this study, we will review your medical 
records to decide if you are eligible for the study.  We may also have to ask you 


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additional questions to determine your eligibility. All subjects will also receive blood and 
urine testing, as well as medical and psychiatric examinations, at the beginning of the 
study to make sure that you can participate in this study. These blood tests may be done 
fasting. This testing may take more than one day. As part of your blood tests you will be 
tested for hepatitis B and hepatitis C. The doctor will inform you that, if your hepatitis 
test is positive, your result must be reported to the New York State Department of Health.  
Female subjects will receive regular pregnancy tests, including a blood pregnancy test at 
the beginning of the study. We will also test you for tuberculosis with a “ppd” skin test. If 
that is positive, or if you have a history of positive ppd skin tests, we may ask you to have 
a chest x ray to decide whether or not you can participate in this study.  
 
We will also ask you whether you would be interested in having some of your rating 
sessions audio or video taped. These procedure would be fully optional and would not 
affect your participation in this study. They are described in more detail below. 
 
Overview of the study 
If you qualify for the study you will be asked to participate in: 
• 3 days of treatment with the research drug (tocilizumab or placebo). The drug is 
infused through a catheter (a small plastic tube) that is placed in a vein in your 
arm using a needle. The infusion is done over 60 minutes. The catheter will be 
placed right before the drug is given to you, and then removed right afterwards. 
• You may participate in this study as an inpatient or outpatient and, overall, will 
take approximately 16 weeks. 
• 4 Clinical, psychological, and medical testing sessions. Some of this testing may 
already have been done as part of the general schizophrenia research study at the 
New York State Psychiatric Institute. If so, those tests will not be repeated and we 
will use the results of those tests for this study. If you have not taken these tests 
before, you will take them as part of your participation in this study. 
• One follow-up visit 2 weeks after you are given tociliuzmab. 
• You will have the option of doing two MRI scans, one at the beginning and one at 
the end of the study. 
 
Drug administration.  A study physician will inject the study drug 
(tocilizumab or placebo) into a vein in your arm very slowly over 60 minutes.  You 
will be watched closely during and after the drug administration. If you have any 
serious side effects to the drug, the injection will be stopped.  A doctor or nurse will 
be present with you at all times during the drug administration to monitor your health. 
 
They study drug (tocilizumab or placebo) will be administered into a vein in your arm 
through a catheter (a small plastic tube). The catheter will be placed right before the 
drug is given to you, and then removed right afterwards. This catheter will be used to 
take blood samples so that we can measure the blood levels of certain chemicals in 
the blood to see if tocilizumab has any effect on these chemicals. We will also check 
for blood levels of your schizophrenia medication. This catheter will be removed 
immediately after you have finished receiving tocilizumab or placebo on that day. 
 
 


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Clinical and Follow-up visits: While you are in this study you will be asked to do 
clinical testing a total of 5 times. These visits will include a medical and psychiatric 
interview, a medical examination, blood samples, urine samples and an EKG.  The goal 
of these follow-up visits is to confirm that the study has not affected your health.  You 
may be asked to participate in more than these follow-up visits if the study physician 
feels it is needed based on the results from your exams. 
 
Psychological and Cognitive testing: You will participate in several psychological 
tests as part of this study at the beginning of the study and at weeks 2, 4, 8, and 12. If you 
have already participated in the general schizophrenia research study at the New York 
State Psychiatric Institute, you may have already finished some of this testing. If so, we 
will use the results of those tests for this study. If you have not taken these psychological 
tests before, you will take them as part of your participation in this study. In addition, we 
will ask you to take a computerized test of your short-term memory.  All together, these 
questionnaires and tests should take about 2-3 hours.  We will be unable to tell you how 
well you do on these tests while you are participating in the study.  However, after the 
study is completed, we can discuss the results of the study with you if you wish. 
 
If you decide to leave the study early, we will ask you to do the follow-up safety 
testing and memory and concentration tests. We will also ask you if you would be willing 
to have your last infusion of the study drug (tocilizumab or placebo) if you have not 
already had it. 
 
 
We will obtain urine tests for drugs of abuse and pregnancy (if you are a female) 
at every visit. 
 
MRI (Magnetic Resonance Imaging). You may also do MRI scans at the 
beginning and end of the study if you would like to. The MRI uses strong magnetic fields 
and radio waves to pictures of your brain.  MRI involved lying on a table that slides into 
a large magnet shaped like a cylinder. Before Beginning the imaging procedure, we will 
ascertain 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 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. Your 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. This testing 
will take a total of 1 hour. 
 
During the MRI scan, you will receive an intravenous injection of a Gadolinium 
compound. Gadolinium compounds are dyes that dissolve in blood and are eliminated by 
the kidneys. Gadolinium compounds do have rare side effects. There are different forms 
of compounds, and we purposefully use the form (MultiHance) that has a low number of 
side effects. One side effect is nausea, observed in 1.8% of people injected with 
MultiHance. A second side effect is hives, observed in 0.7% or people injected with 
MultiHance. Both of these side effects resolve within a few hours.  


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End of the Study Clinical Treatment 
 
You will be able to receive treatment from a psychiatrist and a psychotherapist in our 
outpatient clinic (Lieber Schizophrenia Research Clinic) for at least 4 months after your 
participation in the study, or you may return to your previous treatment provider. The 
treatment in the Lieber Schizophrenia Research Clinic is free except for the cost of 
medications. 
Risks 
1. 
Tocilizumab is FDA approved for individuals with rheumatoid arthritis or 
juvenile idiopathic arthritis. Possible effects of tocilizumab include mild infection 
including nasopharyngitis, high blood pressure, rash, abdominal pain, diarrhea, mildly 
elevated liver blood tests, headache, dizziness, and elevated blood cholesterol levels. 
More serious and uncommon side effects including injection site reaction, low blood 
platelet levels, low white blood cell levels, and tuberculosis if you have already been 
exposed to this infection. Rare side effects that have been observed in individuals who 
take tocilizumab, but may be due to other medications or causes, include gastrointestinal 
perforation, cancer, inflammation of the lining of the lungs, demyelinating disease, and 
heart failure. About 2 in 1000 people who receive tocilizumab may have a severe allergic 
reaction to getting tocilizumab including chills, fever, nausea, and vomiting. Worsening 
of symptoms of schizophrenia is also a possible side effect. Some people develop 
antibodies to tocilizumab. In order to decrease the chance that an adverse event occurs, 
we will do a complete medical test before you receive tocilizumab. We will also monitor 
you closely while you receive the study drug, as well as afterwards. You will not be 
allowed to participate in this study if you have a medical condition that would put you at 
risk of a severe side effect. 
 
2. 
Intravenous Catheter: Mild discomfort can be expected from placement of a 
catheter (which is like a small plastic tube) into a vein with a needle. It may be 
uncomfortable to have an intravenous catheter in your arm. Intra-venous lines can also 
cause bleeding, blockage of the vein, infection or clotting, although these are unlikely 
since the IV will be in your arm for only approximately an hour.  These risks are 
decreased by using proper techniques. In addition, injecting the drug into your vein may 
cause pain or skin irritation at the sites where the drug is injected. 
 
3. 
 Blood samples: A total of about 8 ounces (approximately 17 tablespoons or 
245mL) of blood will be drawn over the study period.  This is less than a typical donation 
to a blood bank, and should not cause any problems. 
 
4. 
Interviews: Sometimes people can feel boredom or frustration while taking 
computer tests or pen and paper tests. You should feel free to tell the research staff 
whenever you feel this way so that they can help you take a break. Research staff will 


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also ask you whether or not you are bored or frustrated and will give you many breaks to 
try to avoid boredom and frustration as much as possible. 
 
5. 
Gadolinium risks:  Gadolinium compounds do have side effects. There are 
different forms of compounds; we use (MultiHance). Common side effects of 
gadolinium: One side effect is nausea and vomiting, observed in less than 2% of people 
injected with MultiHance. If you feel nauseous, please alert staff immediately. Dry mouth 
(less than 2%), dizziness (less than 3.6%), and headache (less than 5%) are possible side 
effects.  An additional side effect is hives, observed in less than 1% of people injected 
with MultiHance. All of these side effects resolve within 20 minutes to several hours. 
People with asthma, allergies, or known sensitivities to dyes are at increased risk for 
more serious side effects (less than 1 in 10,000 injections estimate), such as severe 
allergic reaction that may result in sudden difficulty breathing, and therefore will not be 
injected with Gadolinium.  Rare side effects of gadolinium:  Some patients with bad 
kidney problems have developed a condition known as nephrogenic systemic fibrosis 
(NSF), a serious condition that may be fatal, after receiving gadolinium compounds. You 
will be screened for renal impairment through medical history interview and laboratory 
blood tests. There have been no reported cases of NSF in people who do not have a 
history of kidney failure.  
 
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 or 2 MRI scans with 
gadolinium. 
 
 
6. 
MRI risks: 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 tell the MRI technologist, 
and he or she will stop the scan immediately. In our experience, no one has had 
sensations from the MRI that did not stop when the scanning stopped. 
 
Summary of key safety recommendations 


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• You should refrain from using alcohol, drugs or other medications the 
evening before the study. 
• You should tell us about any past or present medical problems, and about 
use of medications, drugs and alcohol. 
• You should tell us of any history of blood or liver problems, or a history of 
tuberculosis or a positive ppd skin test. 
 
For females of child-bearing age: You cannot participate in this study if you are 
pregnant.  A negative pregnancy test is required to enter the study.  However, since this 
test might not detect the very early phase of pregnancy, you should refrain from sexual 
contact for 15 days before the trial if you are not using a reliable method of birth control.  
Reliable birth control includes oral contraceptive pills or condoms.  You should inform us 
immediately if there is any chance that you may have become pregnant during this time, 
because of the possibility of tocilizumab exposure causing harm to the fetus.  A 
pregnancy test will be performed on the drug administration days. 
 
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 a 
month 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.   
 
Benefits 
 
It is important that you understand that you will receive no personal benefit from 
your involvement in the research itself. The benefits of this research relate primarily to 
understanding the effects of the drug on symptoms of schizophrenia.  This may also help 
to understand the effects of the drug on the brain. You will not have access to this drug 
after you have completed this study. 
 
Costs and Compensation 
For this study, you will receive compensation based on the time that you spend 
during each visit: 
-$50 for each visit when you do not receive study drug (baseline [up to two 
baseline sessions], week 2, 12, 14) and take assessments 
-$100 for each week 0, 4, 8 visit which will involve both assessments and study 
drug 
-$100 for each MRI scan, if you choose to do MRI scans as part of this study. 
-Reimbursement for local transportation 
In total, you will receive up to $550, or $700 if you do the MRI scans.  You will 
be paid by cash or check, which will be mailed to your address 4-6 weeks after the study 


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procedure.  If you do not participate in all the study procedures, your payment will be 
pro-rated based on your participation. 
 
If you earn more than $600, 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 
Research records will be available to research staff, state, federal, and institutional 
personnel, and to the Food and Drug Administration. Records, including signed consent 
forms, will be kept in locked files, and your name will never be used in publications or 
presentations. Electronic data from the study will be stored in a password-protected 
database in the Division of Translational Imaging at New York State Psychiatric Institute. 
Access to this database is limited to investigators and research staff within the Division. 
Additionally, your name and other personal identifying information will be stored in an 
electronically secure database at the New York State Psychiatric Institute. There are legal 
advocacy groups that have authority under State law to access otherwise confidential 
subject records, although they cannot re-disclose this information without your consent. 
The results of your MRI scan will be maintained in an electronically secure database at 
NYSPI and be accessible only to the members of the research team. The coded brain 
imaging data will be shared amongst investigators at NYSPI, CUMC, and Cornell 
medical centers for purposes of brain imaging data analysis. 
 
We will also share only the safety information with Genentech, the makers of 
tocilizumab. Any information that we share with them will only include an identification 
number that does not include any of your personal information and cannot identify you in 
any way. 
 
Research Standards and Participants' Rights 
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 New York State 
Psychiatric Institute or New York Presbyterian Hospital.  On the other hand, it is possible 
that your participation in the study would be terminated without your consent, for 
example if you had a positive pregnancy test.  You will be notified of significant new 
findings that may relate to your willingness to continue to participate. 
 
Compensation for Research Related Injuries 
Federal regulations require that we inform you about our institution's policy with 
regard to compensation and payment for treatment of research-related injuries.  Short 


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term emergency medical treatment, which has been determined to be necessary by New 
York State Psychiatric Institute's doctors, and which is within the capability of New York 
State Psychiatric Institute will be provided.  In addition, we will provide assistance in 
arranging follow up care in such instances. 
New York State Psychiatric Institute and the Research Foundation for Mental 
Hygiene do not provide compensation or payment for treatment of research related 
injuries.  However, you should be aware that participation in this research does not waive 
any of your legal rights to seek such compensation through the courts. 
If you believe that you have sustained injury as a result of participating in a 
research study, you may contact the principal investigator, Dr. Ragy Girgis at 646-774-
5553 so that you can review the matter. 
 
Please be aware that: 
1. 
The New York State Psychiatric Institute and New York Presbyterian 
Hospital will furnish that emergency medical care determined to be necessary by the 
medical staff of these hospitals 
2. 
You will be responsible for the cost of such care, either personally or 
through your medical insurance or other form of medical coverage. 
3. 
No monetary compensation for wages lost as a result of injury will be paid 
to you by the New York State Psychiatric Institute or by New York Presbyterian 
Hospital. 
4. 
By signing this consent form, you are not waiving any of your legal rights 
to seek compensation through the courts. 
 
Questions 
The investigators will answer, to the best of their ability, any questions you may 
have now or in the future regarding study procedures or your response to them.  You can 
call the principal investigator, Dr. Ragy Girgis, at 646-774-5553.  
 
You will be notified of significant new findings that may relate to your 
willingness to continue to participate in this study. 
 
If you have any questions about your rights as a research participant, want to 
provide feedback, or have a complaint, you may call the NYSPI Institutional Review 
Board (IRB). (An IRB is a committee that protects the rights of human subjects in 
research studies). You may call the IRB Executive Director at 646-774-7161 during 
regular office hours.  
 
Please check below to indicate whether or not you want to participate in the MRI 
part of this study. 
 
____  
I am interested in participating in the MRI part of this study. 
 
____  
I am not interested in participating in the MRI part of this study. 
 
Statement of Consent 


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I have discussed this study with the study physician to my satisfaction.  To the 
best of my knowledge, I am not pregnant.  I have been informed that my participation is 
voluntary, and that I can withdraw from the study at any time without prejudice.   
I have read the above and I voluntarily agree to enter this research study.   
 
____________________________  
Signature of Subject  
 
 
 
 
_______________________  
 
 
 
_____________ 
Printed Name of Subject 
 
 
 
 
 
Date 
 
 
Statement of Investigator 
I have discussed the proposed research with this subject and, in my opinion, this 
subject understands the benefits, risks and alternatives (including non participation) and 
is capable of freely consenting to participate in this research. 
 
_______________________  
 
 
 
_____________ 
Signature of Study Physician obtaining consent 
 
 
Date 
 
 
_________________________________ 
Printed Name of Study Physician 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


For Emergencies, call Ragy Girgis, MD 
 
 
at 646-774-5553 
IRB #6729    2/16 
11 
 
 
 
 
 
 
 
 
OPTIONAL: 
Patient Audiotape Consent Form: IRB # 
      
As part of your participation in this protocol, you are being asked to be 
audiotaped during interviews by a member of the research team at the New York State 
Psychiatric Institute.  You may be asked to be audiotaped for some or all of these 
interviews.   
 
The audiotape will be used for educational and research purposes only. These 
tapes are used to teach professionals how to conduct the interviews and to ensure that 
different members of the research team are conducting the same type of interviews 
similarly.  These tapes may be listened to by the researchers and clinicians involved with 
this clinic.   We will keep and use these tapes for up to 10 years 
 
Audiotaping is entirely optional.  If you consent to the audiotape, you can 
withdraw your consent at any time and tapes can be erased during or after the interview. 
If you do not consent, or later decide to withdraw your consent, it will not affect your 
participation in this research protocol or in treatment at the New York State Psychiatric 
Institute in any way.   
 
We will do our utmost to ensure the confidentiality of the audiotape. However, 
there is a slight risk that someone will learn about your personal information after 
listening to this audiotape. To minimize the chances of this happening, the audiotape and 
written material presented with it will not include your name. All audiotapes will be 
strictly confidential and will be kept in locked files.  Only the research staff will have 
access to them, and they will listen to them only for research purposes.    
 
Statement of Consent: 
 
I reserve the right to withdraw this consent at any time. 
 
_________________________________     
 
Patient’s Name (print) 
 
__________________________________  
_______________ 
Patient’s Signature  
 
 
 
Date 
 
I have discussed the proposed audiotaping procedures with this subject and, in my 


For Emergencies, call Ragy Girgis, MD 
 
 
at 646-774-5553 
IRB #6729    2/16 
12 
opinion, this subject understands the benefit, risks and alternatives (including non-
participation) and is freely capable of consenting to participate in the audiotaping 
component of this study. 
 
__________________________________                                 
Signature of person obtaining consent   
 
Print Name   
 
Date  
 
OPTIONAL: 
Patient Videotape Consent Form: IRB # 
 
As part of your participation in this protocol, you are being asked to be 
videotaped during interviews by a member of the research team at New York State 
Psychiatric Institute.  You maybe asked to be videotaped for some or all of these 
interviews. 
 
The videotape will be used for educational and research purposes only. These 
tapes are used to teach professionals how to conduct the interviews and to ensure that 
different members of the research team are conducting the same type of interviews 
similarly.  These tapes may be seen by the researchers and clinicians involved with this 
clinic.   We will keep and use these tapes for up to 10 years 
 
Videotaping is entirely optional.  If you consent to the videotape, you can 
withdraw your consent at any time and tapes can be erased during or after the interview. 
If you do not consent, or later decide to withdraw your consent, it will not affect your 
participation in this research study or in treatment at the New York State Psychiatric 
Institute in any way.   
 
We will do our utmost to ensure the confidentiality of the videotape. However, 
there is a slight risk that someone will learn about your personal information after 
viewing this videotape. To minimize the chances of this happening, the videotape and 
written material presented with it will not include your name. All videotapes will be 
strictly confidential and will be kept in locked files.  Only the research staff will have 
access to them, and they will view them only for research purposes.    
 
Statement of Consent: 
 
I reserve the right to withdraw this consent at any time. 
 
_________________________________     
 
Patient’s Name (print) 
 
__________________________________  
_______________ 
Patient’s Signature  
 
 
 
Date 
 
I have discussed the proposed videotaping procedures with this subject and in my 
opinion, this subject understands the benefit, risks and alternatives (including non-


For Emergencies, call Ragy Girgis, MD 
 
 
at 646-774-5553 
IRB #6729    2/16 
13 
participation) and is freely capable of consenting to participate in the videotaping 
component of this study. 
 
__________________________________                                 
Signature of person obtaining consent   
 
Print Name   
 
Date  


For Emergencies, call Ragy Girgis, MD 
 
 
at 646-774-5553 
IRB #6729    2/16 
14 
CAPACITY ADDENDUM 
 
 
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 decision 
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. Ragy Girgis’ research project: “Tocilizumab, An Il-6 Receptor 
Antibody, As Add-On Treatment For Residual Positive, Negative, And Cognitive 
Symptoms Of Schizophrenia: A Randomized, Double-Blind, Placebo-Controlled 
Clinical Trial” 
 
 
On the basis of my examination, I have arrived at the conclusion that: 
 
 
 
 
 
1) 
This patient has this capacity at this time. 
 
 
 
 
 
2) 
There is a question about this patient's capacity at 
this time. 
 
 
 
 
 
3) 
This patient clearly lacks this capacity. 
 
 
Print Name ________________________________ 
 
 
Signature 
 
 
 
 
 
Date 
 
  
 
 

Prot_000.pdf: 
Protocol Summary Form
6729
Girgis, Ragy
Page 1 of 31
Protocol Title:
Tocilizumab, An Il-6 Receptor Antibody, 
As Add-On Treatment For Residual 
Positive, Negative, And Cognitive 
Symptoms Of Schizophrenia: A 
Randomized, Double-Blind, Placebo-
Controlled Clinical Trial
Protocol Number:
6729
First Approval:
07/09/2013
Expiration Date:
03/03/2018
Version Date:
02/06/2017
Clinic:
Translational Imaging
Contact Principal Investigator:
Ragy Girgis, MD
Email: ragygir@nyspi.columbia.edu
Telephone: 646-774-5553
Co-Investigator(s):
Anissa Abi-Dargham, MD
Alan Brown, MD
Mark Slifstein, PHD
Research Chief:
Anissa Abi-Dargham, MD
Cover Sheet
Choose from the following that is applicable to your study
I am submitting an annual continuation without modifications 
Division & Personnel
Division
What Division/Department does the PI belong to?
Translational Imaging
Within the division/department, what Center or group are you affiliated with, if any? 
Translational Imaging
Unaffiliated Personnel


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Girgis, Ragy
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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.
N/A
Application for Continuation of Research
Status
Current Status of Study: 
Enrollment of new subjects is closed. Research procedures and/or interventions are ongoing for subjects 
currently enrolled.
Summary of Experiences to Date
Please provide a summary of scientific progress of the study and the experience of research participants, to 
date. This requirement is designed to allow for the investigator and the IRB to reassess the study’s risks and 
benefits in terms of developments in the field, changing practice patterns, and new IRB policies and 
procedures.
We have completed enrollment for this study. The last subject will complete her last visit at the beginning of 
2/17. After that time we will proceed with data analysis.
Funding
Have there been any changes in funding status since the prior approval? 
No
Have the principal investigator and other investigators made all required disclosures of financial interest in 
the study sponsor/product?
Yes
Summary
Have there been any study findings, recent literature, or untoward events occuring here or at other sites in 
the past year which might affect the analysis of the safety, risks or benefits of study participation? 
No
Have there been any serious adverse events (serious and/or unanticipated problems involving risks to 
subjects or others at this site which occured in the past year)? 
Yes
Please describe them and indicate resultant protocol modifications made. 
One patient, IL656, stopped his antipsychotic and antidepressant midway through the trial. He developed 
suicidal ideation and was hospitalized. In the hospital, he restarted his medications and recovered promptly. 
He was withdrawn from the trial. There were no sequelae. This was reported to the IRB.
Have all study staff with a significant role in the design or implementation of the human subject components 
of this study received required training in human research subject protections?


Protocol Summary Form
6729
Girgis, Ragy
Page 3 of 31
Yes
Is the study covered by a certificate of confidentiality? 
No
Overall Progress
Approved sample size
75 enrollees, 36 completers
Total number of participants enrolled to date
58
Number of participants who have completed the study to date 
35
Have there been any significant deviations from the anticipated study recruitment, retention or completion 
estimates? 
No
Comments / additional information 
Sample Demographics
Specify population
Schizophrenia
Total number of participants enrolled from this population to date 
58
Gender, Racial and Ethnic Breakdown 
16 F, 42 Males. 35 AA, 18C, 4 M, 1 As; 9 Hispanic
Summary of Current Year's Enrollment and Drop-out 
Number of participants who signed consent in the past year
19
Number of participants currently enrolled
1
Did the investigator withdraw participants from the study? 
Yes
Circumstances of withdrawal:
There were 8 total. 7 were withdrawn as they were screen fails. 1 had the SAE described above.
Did participants decide to discontinue study involvement? 
Yes
Circumstances of discontinuation:
There were 3 total. Two withdrew before any study drug was administered as they decided against doing the 
study. One withdrew after one administration of study drug as he decided he did not want to participate any 
longer.


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Girgis, Ragy
Page 4 of 31
Procedures
To create the protocol summary form, first indicate if this research will include any of the following 
procedures
   Psychiatric Assessment
   Neuropsychological Evaluation
   Collection of Biological Specimens
   Medication Trial
   Use of Placebo or Sham Treatment
   Audio or Videotaping
   Off-label Use of Drug or Device
Population
Indicate which of the following populations will be included in this research
   Adults who may have impaired decision-making ability
   Adults
   Adults over 50
   Individuals with Psychosis
   Inpatients
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
2
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
Foundation
Sponsor
Stanley Medical Research Institute
Select one of the following
Single Site


Protocol Summary Form
6729
Girgis, Ragy
Page 5 of 31
Business Office
CU
Does the grant/contract involve a subcontract? 
No
Funding Source #2
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
Other
Sponsor
irving Institute
Select one of the following
Single Site
Business Office
CU
Does the grant/contract involve a subcontract? 
No
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 
Lay Summary of Proposed Research
Schizophrenia (SZ) is a prevalent, debilitating, and costly illness. Currently available treatments are often 
either only partially effective or associated with significant side effects. Thus, newer treatments are 
desperately required.
All current treatments for SZ function primarily by blocking D2-type dopamine receptors. An alternative 
theory of SZ comes from studies of microbial pathology and SZ that postulate disturbances of cytokines and 
inflammatory mediators in SZ. Ecologic data have suggested associations between early pregnancy 
infection and the development of SZ in offspring of infected mothers. Additionally, lifetime infection with 


Protocol Summary Form
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Girgis, Ragy
Page 6 of 31
Toxoplasma gondii substantially increases the risk of SZ, while epidemiologic data, studies on the effects of 
Toxoplasma gondii infection in humans and rodents, and results of the effects of antipsychotic medications 
on Toxoplasma gondii implicate this organism in risk for SZ.
One of the main mediators of the effects of infection/inflammation in the human body is cytokines. Recent 
data suggest that cytokines, and in particular IL-6, may mediate the effects of lifetime or prenatal infection 
on SZ risk. Preclinical models of SZ support a convergence between a role for IL-6 in the pathophysiology 
of SZ and the major neurochemical hypotheses of SZ-the dopamine and glutamate hypotheses. Namely, IL-
6 dysfunction or excess promotes SZ-like behaviors and SZ-like biochemical and electrophysiological 
profiles, while IL-6 knockout or neutralization mitigates these abnormalities. Furthermore, plasma IL-6 
levels are elevated in acutely psychotic but not treated patients, and Positron Emission Tomography (PET) 
studies have shown active inflammation in the brains of individuals with psychosis. Finally, treatment of 
individuals with SZ with non-specific anti-inflammatory agents, such as celecoxib and aspirin, has 
suggested a role for anti-inflammatory agents in SZ. These data also suggest that studies of immunologic 
agents that more specifically target the underlying pathophysiology of SZ may be more efficacious. 
Tocilizumab (Actemra®) is an FDA-approved humanized monoclonal antibody against the IL-6 receptor 
used for treatment of rheumatoid arthritis in individuals who have not responded to at least one TNF-alpha 
therapy and for juvenile idiopathic arthritis. We will conduct a randomized, placebo-controlled, double-
blind clinical trial of tocilizumab as add-on treatment for residual positive, negative, and cognitive 
symptoms in SZ. After a two-week baseline measurement, a 12-week treatment phase (i.e., three doses of 
study drug), adjunctive to antipsychotics, will begin, with 18 individuals randomly assigned to tocilizumab 
and 18 individuals to placebo. The primary study hypothesis is that individuals receiving tocilizumab will 
show greater improvements in their PANSS total scores than those taking placebo. Secondary outcomes will 
include comparisons on specific clinical, cognitive, and biochemical (i.e., cytokines) outcomes, as well as 
relationships between baseline IL-6 levels and treatment outcome. To our knowledge, this is the first 
investigation of immune modulation as a treatment in SZ and the first direct test of the 
immunologic/inflammatory/infectious theory of SZ, and therefore has great implications for the study of 
drug development, etiology and pathophysiology of the illness.
Background, Significance and Rationale
Background, Significance and Rationale
Birth cohort studies have identified associations between schizophrenia (SZ) and early pregnancy exposure 
to infectious agents, including influenza (Brown, Begg et al. 2004), herpes simplex virus type 2 (Buka, 
Tsuang et al. 2001; Buka, Cannon et al. 2008), and Toxoplasma gondii (Brown, Schaefer et al. 2005; 
Mortensen, Norgaard-Pedersen et al. 2007). The most parsimonious model suggests that there are common 
effects of infection that may increase the risk of SZ (Brown and Derkits 2010). These effects are 
hypothesized to be mediated by cytokines (Gilmore and Jarskog 1997). Cytokines are a family of soluble 
proteins that play an important role as the systemic mediators of host response to infection (Brown and 
Derkits 2010). Cytokines, including interleukin-6 (IL-6), may be produced in the CNS, have numerous 
effects on both glial and neuronal components of the CNS and have effects on both normal and abnormal 
brain development (Frei, Malipiero et al. 1989; Benveniste, Sparacio et al. 1990; Hopkins and Rothwell 


Protocol Summary Form
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Girgis, Ragy
Page 7 of 31
1995; Rothwell and Hopkins 1995; Gilmore and Jarskog 1997). In the maternal immune activation model of 
SZ, lipopolysaccharide- and poly (I:C) administration induce elevated levels of IL-6 in fetal brain (Patterson 
2009). IL-6 levels are elevated in the plasma of both first-episode (effect size = 1.4) and acute relapsed 
(effect size = 0.96) patients, while they decrease after treatment (effect size = -0.31) (Miller, Buckley et al. 
2011). These data suggest that IL-6 is a state marker of SZ, normalizing with treatment.  In addition, 
Positron Emission Tomography (PET) studies of the peripheral benzodiazepine receptor, which is 
upregulated during microglial activation, have also supported persistent inflammation in the brains of 
individuals with SZ (van Berckel, Bossong et al. 2008; Doorduin, de Vries et al. 2009; Takano, Arakawa et 
al. 2010). Finally, treatment studies of non-specific anti-inflammatory agents also support the development 
of treatments aimed at underlying inflammation (Muller, Riedel et al. 2002; Akhondzadeh, Tabatabaee et al. 
2007; Laan, Grobbee et al. 2010; Muller, Krause et al. 2010). Therefore, pharmacologic agents that potently 
inhibit the activity of specific cytokines, in particular IL-6, represent a novel approach to the treatment of 
schizophrenia and may offer greater therapeutic benefit. 
Specific Aims and Hypotheses
Specific Aims and Hypotheses
Study Goals:
1) Establish the feasibility of using tocilizumab, and targeting the IL-6 receptor in general, as treatment for 
positive, negative and cognitive symptoms and impairments in daily functioning in SZ (i.e., as measured by 
PANSS, GAF, CGI, UPSA, and MATRICS) and determine effect sizes for a more definitive clinical trial.
2) Refine the study procedures and inclusion/exclusion criteria for a future, definitive clinical trial, using 
clinical/neuropsychological measures and laboratory analyses of cytokine levels.
3) To evaluate the safety of tocilizumab in schizophrenia.
 
4) To examine the effects of tocilizumab on hippocampal CBV and glutamate.
Description of Subject Population
Sample #1
Specify subject population
Schizophrenia, Schizoaffective Disorder
Number of completers required to accomplish study aims
36
Projected number of subjects who will be enrolled to obtain required number of completers
75


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Age range of subject population
18-59
Gender, Racial and Ethnic Breakdown
Based on the expected breakdown from 5-South and the Lieber Schizophrenia Research Clinic, we expect to 
enroll 65% males and 35% females; with a racial profile of 44% Caucasian, 22% Hispanic, 26% African 
American, 6% Asian, and 2% Other.
Description of subject population
Patients with Schizophrenia or schizoaffective disorder. All will undergo a screening history and physical, 
structured diagnostic interview, baseline laboratory work, and a urine drug screen. We will use the available 
information already obtained on subjects via clinical admission procedures or participation in other research 
protocols whenever possible.
Recruitment Procedures
Describe settings where recruitment will occur
Patients are recruited from various sources by referral from departments of the Columbia University 
Medical Center (CUMC) and from affiliated hospitals (Harlem Hospital Center and St. Luke’s-Roosevelt) and 
local mental health clinics, day programs, community residences, family and mental health advocacy 
groups.
We could also recruit stable, English-speaking patients from outpatient clinics, from the Inwood or 
Audubon Clinics of the Washington Heights Community Service, or from the Lieber Research Clinic if they 
meet criteria for participation and are willing to participate. We could also recruit individuals who are 
inpatients on the 5-South inpatient unit at NYSPI, the 4-South inpatient unit at PI, or other inpatient units, 
if the patients meet criteria for the study, have capacity to make informed consent, and are interested in 
participating in this study.
In other terms this study can be conducted on an inpatient or outpatient basis but recruitment could be 
from either the inpatient or the outpatient settings. The patient will be approached by a member of the 
clinical team for permission to be approached by the research team. Capacity to provide informed consent 
will be evaluated by a psychiatrist not associated with the research team.  
How and by whom will subjects be approached and/or recruited? 
see above
How will the study be advertised/publicized? 
NYSPI IRB approved advertisements/flyers may be posted in local or national media (e.g., Village Voice), 
Internet, other electronic media, or on bulletin boards or distributed at locations described above.
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
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Girgis, Ragy
Page 9 of 31
NCT02034474
Concurrent Research Studies
Will subjects in this study participate in or be recruited from other studies? 
Yes
Describe concurrent research involvement
We will also recruit patients who are actively participating in #6334R (Schizophrenia Research Clinic (LSR) 
Outpatient Umbrella Protocol) or in #6691 MOSAIC: THE MANAGEMENT OF SCHIZOPHRENIA IN
CLINICAL PRACTICE A Prospective, Non-interventional Registry of Diverse Patients with
Schizophrenia Across the Disease Spectrum in Usual Care Settings: Course of Disease,
Treatments, and Burden of Illness
Inclusion/Exclusion Criteria
Name the subject group/sub sample
Patients
Create or insert table to describe the inclusion criteria and methods to ascertain them
Criteria
Assessment
1. Males or females between 18 and 59 years old
History
2. Fulfill DSM-IV criteria for schizophrenic illness, 
schizoaffective disorder
Per history, clinical impression 
SCID and/or DIGS criteria
3. A negative urine toxicology
Urine toxicology
4, Capacity to understand the study and to give written informed consent
History and clinician’s assessment
5. Must be on a stable dose of any combination of antipsychotic medications, up to two 
medications, except for clozapine, for at least 4 weeks if oral or 2 cycles if depot prior 
to the study. Mood stabilizers, benzodiazepines and antidepressants are allowed as long 
as the drugs have not been changed for 4 weeks before screening.
History
6. Moderate level of symptomatology
PANSS > 60
Create or insert table to describe the exclusion criteria and methods to ascertain them
Criteria
Assessment


Protocol Summary Form
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Girgis, Ragy
Page 10 of 31
1. Pregnancy or lactation, lack of effective birth control during the 15 days before 
the initial day of the study (Day 0) and for the duration of the drug trial
Blood pregnancy test, assessment
2. Unstable medical or neurological condition ( Uncontrolled disease states, such 
as asthma, psoriasis, or inflammatory bowel disease, where flares are commonly 
treated with oral or parenteral corticosteroids , ANC < 1500, platelet count < 
120,000, severe liver disease or AST/ALT greater than 1.5 times the ULN at 
baseline, a current severe infection, intestinal diverticula, or tuberculosis (latent 
or active-patients with a positive ppd but negative chest x ray may participate)), 
or a live vaccine within one month of receiving study drug.
Medical and neurological history, EKG, blood 
chemistry, ppd
3. Any current non medicinal use of amphetamines, opiates, cocaine, sedative-
hypnotics, cannabis, or other psychoactive drugs (other than nicotine)
History, urine toxicology
4. Currently taking a medication known to cause neutropenia (clozapine, 
carbamazepine), or another disease modifying anti-rheumatic drugs (DMARD)
History
5. Any history of substance dependence (other than nicotine or cannabis) within 
the previous 6 months or a history of substance abuse within the previous 1 
months (other than nicotine) 
History
6. Impaired intellectual functioning 
WTAR < 6 (will only be obtained if there is a history 
of impaired intellectual functioning or if a study 
physician feels that the study subject may have 
impaired intellectual functioning; it will not be 
obtained if there is no indication of impaired 
intellectual functioning)
7. Major surgery (including joint surgery) within 8 weeks prior to screening or 
planned major surgery within 6 months following randomization.
History
8. Treatment with any investigational agent within 4 weeks (or 5 half-lives of the 
investigational drug, whichever is longer) of screening
History
9. Previous treatment with any cell-depleting therapies, including investigational 
agents or approved therapies, some examples are CAMPATH, anti-CD4, anti-
CD5, anti¬CD3, anti-CD19 and anti-CD20.
History
10. Treatment with intravenous gamma globulin, plasmapheresis or Prosorba 
column within 6 months of baseline.
History
11. Previous treatment with tocilizumab (an exception to this criterion may be 
granted for single dose exposure upon application to the sponsor on a case-by-
case basis).
History
12. Any previous treatment with alkylating agents such as chlorambucil, or with 
total lymphoid irradiation.
History
13. History of severe allergic or anaphylactic reactions to human, humanized or 
murine monoclonal antibodies.
History


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Girgis, Ragy
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14. Evidence of serious uncontrolled concomitant cardiovascular, nervous system, 
pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine 
(include uncontrolled diabetes mellitus) or gastrointestinal disease (including 
complicated diverticulitis, ulcerative colitis, or Crohn’s disease.)
History, labs, EKG
15. Current liver disease as determined by principal investigator unless related to 
primary disease under investigation 
History, labs
16. Known active current or history of recurrent bacterial, viral, fungal, 
mycobacterial or other infections (including but not limited to tuberculosis and 
atypical mycobacterial disease, Hepatitis B and C, and herpes zoster, but 
excluding fungal infections of nail beds).
History, labs
17. Any major episode of infection requiring hospitalization or treatment with IV 
antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks prior to 
screening.
History
18. Active TB requiring treatment within the previous 3 years. Patients will be 
screened for latent TB and, if positive, treated following local practice guidelines 
prior to initiating tocilizumab. Patients treated for tuberculosis with no 
recurrence in 3 years are permitted.
History, ppd
19. Primary or secondary immunodeficiency (history of or currently active) unless 
related to primary disease under investigation.
History, labs
20. Evidence of active malignant disease, malignancies diagnosed within the 
previous 10 years (including hematological malignancies and solid tumors, except 
basal and squamous cell carcinoma of the skin or carcinoma in situ of the cervix 
uteri that has been excised and cured), or breast cancer diagnosed within the 
previous 20 years unless related to primary disease under investigation.
History
21. Neuropathies or other conditions that might interfere with pain 
evaluation unless related to primary disease under investigation.
History
22. Patients with lack of peripheral venous access.
Physical exam
23. Body weight of > 150 kg.
Weight
24. Serum creatinine > 1.6 mg/dL (141 µmol/L) in female patients and > 1.9 
mg/dL (168 µmol/L) in male patients. Patients with serum creatinine values 
exceeding limits may be eligible for the study if their estimated glomerular 
filtration rates (GFR) are >30.
Labs
25. Total Bilirubin > ULN 
Labs
26. Hemoglobin < 85 g/L (8.5 g/dL; 5.3 mmol/L) 
Labs
27. White Blood Cells < 2.5 x 109/L (3000/mm3)
Labs


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Girgis, Ragy
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28. Absolute Lymphocyte Count < 0.5 x 109/L (500/mm3)
Labs
29. Positive Hepatitis BsAg, or Hepatitis C antibody
Labs
Additional Exclusion Criteria for MRI Portion
 
1. Metal Implants or a history of metal working
Physician evaluation
2. Lifetime diagnosis of asthma with asthmatic symptoms within the past 3 years
Physician evaluation
3. Lifetime diagnosis of renal failure or renal disease
Physician evaluation
4. Lifetime diagnosis of hypertension or diabetes
Physician evaluation
5. 
Renal 
insufficiency 
(Crcl 
<50mL/min/1.73m2) 
Crcl=[[140-
age(yr)]*weight(kg)]/[72*serum Cr(mg/dl)]
Serum Cr and formula
 6.More than one previous gadolinium scan
 History
 
For females of child bearing age:
 
The pregnancy test is performed during the screening procedure and repeated every day study drug is 
administered.
Waiver of Consent/Authorization
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 
No
Waiver of parental consent 
No


Protocol Summary Form
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Consent Procedures
Is eligibility screening for this study conducted under a different IRB protocol?
No
Describe procedures used to obtain consent during the screening process 
The consent process is a multistep process, whereby information about the risks and benefits of the study 
will be provided to potential subjects across several sessions. The number of sessions over which this 
information will be provided will depend on how well the subject understands and retains the information. 
The process begins with the subject initiating contact via telephone. The research staff will provide a brief 
description of the study. Thereafter, potentially eligible candidates are scheduled for a face-to-face 
interview. Subjects will be informed of all potential risks and benefits of participation. Subjects will be 
required to read the informed consent form, and the investigator additionally describes the risks and 
discomforts. 
 
Describe Study Consent Procedures
 See above.
Indicate which of the following are employed as a part of screening or main study consent procedures
   Consent Form
Persons designated to discuss and document consent
Select the names of persons designated to obtain consent/assent
Brown, Alan, MD
Girgis, Ragy, MD
Type in the name(s) not found in the above list
Independent Assessment of Capacity
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
Any licensed psychiatrist (MD) or psychologist (PhD) who works in the New York State Psychiatric Institute and has completed 
CITI training may assess capacity.
Study Procedures


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Page 14 of 31
Describe the procedures required for this study
Subjects will be randomized to the two groups (i.e., placebo or tocilizumab).  Patient assignment will be 
performed by Mark Slifstein, PhD, who has no contact with the patients.  The drug and placebo will be 
identically packaged. 
 The study will involve (summarized in table 1):
-           A screening assessment (only tests that are not already acquired will be performed.  No tests will be 
repeated).  These  procedures may be done on more than one day. 
-           3 total days of treatment with placebo or tocilizumab
-           2 safety follow up visits (e.g. safety tests, EKG)*
* If necessary, patients could return for a further follow up visit 2 weeks after study completion.
Table 1) Timetable of phase II of the study
 
TABLE 1: PROCEDURES
Study Week
Screeninga
0
2
4
8
12
14b
Informed Consent
X
 
 
 
 
 
 
Study Drug
 
X
 
X
X
 
 
Efficacy Aims
PANSS
X
 
X
X
X
X
 
CGI/GAF
X
 
X
X
X
X
 
MATRICS/UPSA
X
 
X
X
X
X
 
Safety Aims
SMA20/CBC/TSH/C-SSRS/Urinalysis
X
 
X
X
X
X
X
Physical Exam
X
 
X
X
X
X
X
Vitals
X
X
X
X
X
X
X
SAFTEE
X
X
X
X
X
X
X
SAS/EKG
X
 
 
X
X
X
X
Cytokine Levels/Toxoplasma Ab
X
 
 
X
X
X
 
Urine Toxicology/Pregnancy
X
X
X
X
X
X
X
MRI (optional)
 
X
 
 
 
X
 
a A WTAR will be performed for any individuals suspected of having intellectual impairment.
b These procedures will be performed only if there were abnormalities from the Week 12 assessments that require follow up.
Specific procedures.
Screening.


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Patients will receive the routine clinical characterization. Study subjects will be initially evaluated with a 
medical history, review of symptoms, and physical and neurological exam to determine if an underlying 
treatable medical condition is prohibiting the use of tocilizumab.  Laboratory studies will be obtained to 
exclude metabolic or neuroendocrine disturbances, specifically TSH, electrolytes, CBC, LFTs, BUN, fasting 
lipid panel, hepatitis panel, urinalysis, and creatinine.  If medical review of systems suggests HIV risk 
factors, then an HIV test will be obtained.  If an HIV test is obtained, a study physician will provide pre- and 
post-test counseling.
All patients will also receive a ppd test. Patients with positive ppd tests may receive a chest x ray to rule out 
TB. Patients who have known positive ppds may have a chest x ray without placing an additional ppd. 
 
Neuropsychological Test Battery and clinical assessment.
Baseline assessments
To obtain a research diagnosis, we will use the SCID and/or DIGS information, in addition to history and 
clinical impression.  Additional information will be collected through the Positive and Negative Syndrome 
Scale (PANSS) (Kay et al., 1987), the Clinical Global Impression (CGI) scale (Guy 1976), WTAR (WTAR 2001), 
Global Assessment of Functioning (GAF) (APA, 2000), the University of California Performance-based Skills 
Assessment (UPSA) (Patterson et al., 2001) and the Columbia Suicide Severity Rating Scale (C-SSRS) (Posner 
et al., 2007).
Clinical assessment
Clinical assessment will be performed at baseline and weeks 2, 4, 8, and 12. At each time, PANSS, the CGI 
scale, the GAF, CSSRS, MATRICS, and UPSA will be performed.
Neuropsychological Test Battery
The MATRICS battery was chosen by a panel of experts on cognition in schizophrenia, and the battery is 
specifically designed to assess treatment-related changes in cognition in patients with schizophrenia. It 
assesses cognitive functions in the following domains using the following tests: Speed of Processing: 
Category Fluency, Brief Assessment of Cognition in Schizophrenia (BACS) – Symbol-Coding, Trail Making A. 
Attention/Vigilance: Continuous Performance Test – Identical Pairs (CPT-IP). Working Memory: University 
of Maryland – Letter-Number Span, Wechsler Memory Scale (WMS) - III Spatial Span. Verbal Learning: 
Hopkins Verbal Learning Test (HVLT) – Revised. Visual Learning: Brief Visuospatial Memory Test (BVMT) ¬– 
Revised. Reasoning and Problem Solving: Neuropsychological Assessment Battery (NAB) – Mazes. Social 
Cognition: Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT)– Managing Emotions.  This battery 
takes 60 to 90 minutes to administer.
Study Drug administration


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At day 0, week 4 and week 8 subjects will receive study drug (placebo or tocilizumab) based on random 
assignment. Study drug will be administered intravenously via an iv drip over 60 min as per clinical 
guidelines. Blood pressure and heart rate will be obtained before and after administration. A study 
physician or nurse will be present during the administration. The infusion will take place in the clinical 
room of the Division of Translational Imaging, the ECT suite, or the 5 South treatment room. A study 
physician will be present for the entire infusion.
All subjects randomized to tocilizumab will receive 8mg/kg during their infusions, unless the subject is 
experiencing side effects that, in the opinion of the subject and study physician, are intolerable and likely 
to improve at a lower dose. In these cases 4mg/kg of tocilizumab, or the placebo equivalent, will be 
administered. Placebo will consist of a normal saline solution and will be administered in a similar manner. 
The maximum dose used will be 800mg.
Because of the very low risk of anaphylaxis (see figure for criteria), as well as fever, chills, nausea, or 
vomiting due to the tocilizumab infusion itself (hypersensitivity reaction), the study physician will have 
parenteral epinephrine and diphenhydramine available during each administration, as well as 
acetaminophen, and patients will be monitored by a study physician or nurse for one hour after the 
administration. Patients will also be called by the study physician the day after their administration to 
check in on their status.
 
All patients will provide samples for anti-tocilizumab antibody testing at baseline and at termination.  In 
addition, samples for PK/PD will be tested for each time point when an anti-tocilizumab antibody test is 
done.  All patients experiencing events related to serious hypersensitivity or anaphylactic reactions that 
cause the patient to be withdrawn from study drug treatment will have anti-tocilizumab and PK/PD testing 
at time of event, and also 6 weeks after the last dose for anti-tocilizumab and PK/PD testing.   
Patients withdrawn from study drug due to a reduced neutrophil count will be monitored for signs of 
infection, with treatment as deemed appropriate by the PI or sponsor, and will have a repeat white blood cell 
count with differential performed weekly until the ANC is above 1500 cells/mm3 (1.5 x 109/L). If the ANC 
drops below 1.0 *10^9/L, biweekly CBCs will be performed and a heme consult will be obtained. In 
addition, if the ANC does not return to above 1000 cells/mm3 (1.0 x 109/L) within 2 months (or sooner if 
deemed necessary by the sponsor or PI), a hematology referral will be obtained.
Patients withdrawn from study drug due to a reduced platelet count will have a repeat platelet count 
performed weekly until the count is above 100,000 cells/mm3 (100 x 109/L). If the platelets do not return to 
above 100,000 cells/mm3 (100 x 109/L) within 2 months (or sooner if deemed necessary by the sponsor or 
PI), a hematology referral will be obtained.
 
Patients withdrawn from study drug due to elevated liver function tests will have repeat tests performed, as 
clinically appropriate, until levels return to baseline.  If the patient’s liver function tests have not returned to 


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baseline within 6 months (or sooner, if deemed necessary by the sponsor or designee), an ultrasound and/or 
liver biopsy will be considered.
 
Safety monitoring and follow-up visits
Safety monitoring will include the procedures described above in addition to a full evaluation including the 
following: a complete medical and psychiatric interview, medical exam, extrapyramidal symptoms, routine 
blood tests (25 mL) with LFTs and lipids and EKG and urine at weeks 2, 4, 8, and 12. If clinically indicated, 
subjects may be asked to participate in extra follow-up visits as determined by the study physician. Vital 
signs urine toxicology, urine pregnancy, and adverse events via the SAFTEE will be assessed at every visit.
All patients who participate in this protocol will be managed by a study physician. If a subject who 
participates in this protocol has another psychiatrist before beginning the study, the study physician will 
coordinate care with that psychiatrist, although all patients will be seen for medical/psychiatric assessments 
at a minimum as per the schedule described above. 
 
Patients withdrawn from study drug due to a reduced neutrophil count will be monitored for signs of 
infection, with treatment as deemed appropriate by the PI or sponsor, and will have a repeat white blood cell 
count with differential performed weekly until the ANC is above 1000 cells/mm3 (1.0 x 109/L). If the ANC 
does not return to above 1000 cells/mm3 (1.0 x 109/L) within 2 months (or sooner if deemed necessary by 
the sponsor or PI), a hematology referral will be obtained.
Patients withdrawn from study drug due to a reduced platelet count will have a repeat platelet count 
performed weekly until the count is above 100,000 cells/mm3 (100 x 109/L). If the platelets do not return to 
above 100,000 cells/mm3 (100 x 109/L) within 2 months (or sooner if deemed necessary by the sponsor or 
PI), a hematology referral will be obtained.
Patients withdrawn from study drug due to elevated liver function tests will have repeat tests performed, as 
clinically appropriate, until levels return to baseline.  If the patient’s liver function tests have not returned to 
baseline within 6 months (or sooner, if deemed necessary by the sponsor or designee), an ultrasound and/or 
liver biopsy will be considered.
Early Termination Visits
In the case that patients must terminate the study early, every effort will be made to obtain the next 
scheduled clinical/neuropsychological/safety assessments as soon as possible after early termination, as 
well as the next study drug administration if it has been at least 3 weeks since the last administration and 
continue through the protocol, if possible and if they are willing to do so, as per the regular schedule.
 Audio/Videotaping Option


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Patients who participate in this protocol may be asked to consider having a clinical/neuropsychological 
rating session associated with this study audio or videotaped, and would sign a separate consent for this. 
These audio/videotapes will be used only for educational/training purposes. Any patient who declines will 
still be eligible to participate in all other components of this study. Audio/video tapes will be kept for up to 
ten 10 years. They will be kept in locked file cabinets, and available only to research staff.
Cytokine and Toxoplasma Levels
At the baseline and week 4, 8, and 12 visits, blood will be obtained for cytokine levels and toxoplasma 
antibody.
MRI Option
 
Patients who meet the additional MRI exclusion criteria and are interested will be presented the optoin of 
participating in the MRI option. Of note, participating in the MRI option is not required to be a part of the 
clinical trial. This will be clearly stated to patients.
 
For this option, patients will receive an MRI scan (as detailed below) at baseline and within one month of 
receiving their last dose of study drug. If they terminate early and after receiving at least one dose of study 
drug, they will be asked to have their follow up MRI scan.
 
MRI with gadolinium contrast. Subjects will obtain MRI images on the NYSPI 3.0T GE scanner. CBV, 
ASL, and MRS sequences will be obtained. After a T1 scout image, needed to determine patient position, 
we will acquire the following images:
(1) Standard structural images will be used to obtain tissue content information needed to convert the ASL 
signal into CBF value in physiological units. Next, pseudo Continuous ASL (pCASL) images will be 
acquired. Total imaging time for ASL will be ~10mins.
(2) For acquisition of left hippocampal glutamate using MRS, we will use standard MRS sequences. Total 
imaging time for MRS will be 15~30min.
(3) For CBV mapping, subjects will receive pre-gadolinium and post-gadolinium T-1 weighted images after 
receiving I.V. gadolinium (0.1mmol/kg). Total imaging time for CBV will be ~20 min.
 
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 Dr. Girgis. Images will be read for gross 
structural brain abnormalities by neuroradiologist within one month of the scan. Should there exist a gross 
structural brain abnormality, a neuroradiologist will immediately inform the principal investigator Dr. 
Girgis. 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. Appropriate follow-up with the patients primary care 
physician or appropriate sub-specialist and care setting will be immediately arranged for further diagnostic 
testing/treatment recommendations by Dr. Girgis in consultation with the neuroradiologist. For routine scans 
with no findings, the subject will be informed of the result by letter if they choose or through reviewing the 
letter’s findings with Dr. Girgis at a research follow-up appointment.
 
Additional Gadolinium Information


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Because of the FDA safety announcement, we will inform all subjects who are currently enrolled, 
about this new safety announcement. We will use the following template to begin the discussion:
 
"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."
 
From this point we will have a discussion with the subject about his/her willingness to continue to 
participate. If they do not want to continue their participation, they will be discontinued from the 
study.
 
In addition, to ensure that individuals are systematically queried about previous gadolinium scans, we 
will ask all individuals who are currently enrolled or interested in the study whether they had an MRI 
with an i.v. injection (i.e., “Did they give you an injection?”) in case people do not know the term 
“gadolinium.”  
You can upload charts or diagrams if any
Criteria for Early Discontinuation  
Criteria for Early Discontinuation
Subjects will be withdrawn from the study if:
a. They request it for any reason
b. The PI judges that it is medically unwise to continue in the study, including, but not limited to for severe 
rash, infection, or other side effect
c. ANC < 1000
d. AST/ALT > 3x Upper limit of normal
e. Platelet count < 100,000
f. His/her psychiatric condition deteriorates to the point that he/she loses capacity to consent for this trial. 


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Blood and other Biological Samples
Please create or insert a table describing the proposed collection of blood or other biological specimens
Baseline, Weeks 
4, 8, and 12 Visits
Weeks 0, 2 and 14 
Visits
Total (mL)
Total (oz)
Total (tablespoons)
50mL per visit * 4 
visits = 200mL
15mL per visit * 3 
visits = 45mL
245mL
8.28
16.57
 
Table 2 summarizes blood sampling (mL) over the course of the study for each procedure. The total blood 
sampled is 245 mL, over a 90 day period, which is less than a typical blood donation (500 mL). In the 
consent form, volumes are given in mL, ounces (1 ounce = 29.5 mL) and tablespoons (1 tablespoon = 15 
mL), with all volumes rounded up to the next integer.
 
Assessment Instruments
Create a table or give a brief description of the instruments that will be used for assessment
CGI-3 minutes
GAF-3 minutes
CSSRS-5 minutes
MATRICS-60-90 minutes 
PANSS-15-30 minutes 
UPSA-5 minutes
SCID-60 minutes
DIGS-90 minutes
WTAR-5 minutes


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Please attach copies, unless standard instruments are used
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 
tocilizumab
Manufacturer and other information
 Manufactured by Chugai/Roche. FDA approved for the treatment of rheumatoid arthritis in individuals who 
have not responded to at least one TNF-alpha therapy and for juvenile idiopathic arthritis. We will apply for 
an IND with exemption from the FDA.
Approval Status
No IND is required
Choose one of the following options
FDA has determined that IND is not required
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
Patients will continue on their medication regimen as before the study as long as it is clinically indicated. 
The treating clinician can make changes if needed due to clinical deterioration or side effects. All patients 
who complete the study will be offered at least 4 months of free treatment (free except for the cost of 
medications) with a psychiatrist and psychotherapist in the Lieber Schizophrenia Research Clinic. They will 
also be offered referrals to other providers if they request them.
Clinical Treatment Alternatives
Clinical treatment alternatives
Patients who do not participate in this study may receive their normal clinical care, including with 


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medications, therapy, and other interventions. Biological agents, such as tocilizumab, are available for use 
but have not yet been studied in individuals with schizophrenia.
Risks/Discomforts/Inconveniences 
Risks that could be encountered during the study period
a. Tocilizumab administration
Tocilizumab is FDA-approved for the treatment of rheumatoid arthritis in individuals who have not 
responded to previous DMARD therapy, as well as for juvenile idiopathic arthritis. Therefore, there is 
substantial information on tocilizumab use, and tocilizumab has been found to be generally well tolerated, 
and its risks well characterized. We would also like to clarify that individuals who have received 
tocilizumab in clinical studies or in practice are generally more medically infirm (tocilizumab is indicated 
only for adults who have failed another biologic agent) and often receiving another immune modulator, such 
as methotrexate. Therefore, their risks of side effects are generally much higher than for our subjects who 
will be medically healthy and only receiving tocilizumab. A substantial proportion of serious side effects 
that occur while taking tocilizumab occur in individuals who are already immunocompromised, have CHF, 
or are predisposed or already have cancer.
There are several risks of tocilizumab use. Risks of the administration include anaphylaxis (0.4%) as well as 
an acute hypersensitivity reaction (0.2%) including chills, fever, nausea, and vomiting. The emergence of 
anti-tocilizumab antibodies has been reported in clinical studies (RA: 18 of 601 patients (3.0 %), pJIA: 1 of 
19 patients (5.3 %), sJIA: 11 of 128 patients (8.6 %); and Castleman’s disease: 1 of 35 patients (2.9%).
Common and mild side effects of tocilizumab administration including mild infection including 
nasopharyngitis, hypertension, rash, abdominal pain, diarrhea, mild elevated AST/ALT, headache, and 
dizziness, elevated lipids. More serious side effects including injection site reaction (5-8%), gastrointestinal 
perforation (rare), thrombocytopenia (1.3-1.7%), neutropenia (1.8-3.4%), tuberculosis (rare), upper 
respiratory tract infection (6-8%), cancer (rare, and does not separate from placebo, Lopez-Olivo et al., 
2012), other serious/opportunistic infection (rare), demyelinating disorders (rare, unclear if related to 
tocilizumab), pleurisy (rare), cardiac failure (rare; and in meta-analyses with other immune modulators, 
does not separate from placebo (Singh et al., 2011).
Tocilizumab should not be administered to pregnant or nursing females.
We will also break the blind after 5 subjects and report to the IRB in order to determine whether or not there 
are any psychiatric side effects of tocilizumab.
 
Elevated levels of IL-6 have been known to inhibit CYP450 enzymes, with a preference for those NOT 
involved in the metabolism of antipsychotic medications (e.g., CYP3A4). Treatment with tocilizumab has 
been known to restore CYP450 functioning to normal levels in situations in which elevated IL-6 levels were 
inhibiting CYP450 enzymes, but has not been known to over stimulate these enzymes. Most psychiatric 


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medications are metabolized by CYP450 enzymes NOT affected by IL-6 to a great degree (e.g., CYP2D6), 
although some are metabolized to a minor degree by CYP450 enzymes affected by IL-6 (e.g., CYP3A4). 
Therefore, while we do not expect a change in antipsychotic blood levels during the course of this trial, we 
will be vigilant about monitoring for a change in mental status of all participants in this trial. 
 
There is also the possibility that patients will experience an exacerbation of symptoms while in this trial.
b. Venous Blood sampling
Intra-venous sampling or lines (heplock or IV) can cause bleeding, occlusion, infection, or clotting. They 
may also cause discomfort.
c. Interviews
Patients may experience boredom and fatigue during the administration of neuropsychological 
assessments and ratings scales.
d. Audio/videotaping
There is a slight risk of loss of confidentiality to subjects who participate in this optional component of the 
protocol.
e. 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 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.
 
f. Gadolinium compounds do have side effects such as 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 Multihance (0.7% 
estimate). All of these side effects resolve within 20 minutes to several hours. People with asthma or 


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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.
 
The dosing guidelines are as follows: CNS (Central Nervous System) Adults: The recommended dose 
of Multihance 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 


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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 after finishing study drug 
administrations at least one month to three months 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. 
Describe procedures for minimizing risks
All subjects are given contact information for the PI and study physician (primarily Dr. Girgis) so that they 
can contact him at any time if necessary.
a. In order to minimize risk, each patient will be monitored and the drug infusion stopped immediately 
should there be any safety concern. We will obtain frequent laboratory analyses, including lipids, liver 
tests, and cbc, adverse event queries, and EKGs during this study.  Patients will be terminated from the 
study if their LFTs (i.e., AST/ALT) rise above 3x ULN or the ANC below 1000 or platelet count <100,000, or 
they develop side effects that are, in the opinion of the PI, preclusive of continuing in this protocol. 
Patients with baseline severe liver disease, elevated AST/ALT (1.5x ULN), ANC<1500, thrombocytopenia 
(platelet < 100,000), known intestinal diverticula or an immunologic disorder which impairs the immune 
system will be excluded from this study. Patients will be instructed not to obtain any live vaccines between 
1 month before the study and 3 months after receiving study drug. All patients will have a ppd before 
beginning study drug administration, and positive ppds will be followed by chest xrays. Subjects with 
positive ppds and active disease or latent disease will not be included in this study, subjects with positive 
ppds and negative chest x rays may be included.
 
These criteria will ensure that the safety of the subjects who participate in this trial is maximized and will 
not increase the risks to subjects. There are are additional general and specific safeguards in place to 
maximize the safety of all individuals of this trial, as well as several important safety considerations.
 
First, the vast majority of the data on tocilizumab related neutropenia, transaminitis, and thrombocytopenia 
were obtained in very medically infirm patients on both tocilizumab and another DMARD (often 
methotrexate or prednisone which are comparatively more toxic). Therefore, all of the side effects that we 
will be discussing here are likely to occur at lesser rates and with lesser severity than described. In addition, 
tocilizumab is widely approved and it is now not possible to quantify the number of people who have 
received it. In addition, while the maximum dose in this trial is 8mg/kg given every 4 weeks, 12mg/kg is 
routinely given every 2 weeks to children with arthritis, attesting to the relative safety of this medication. 
Similarly, the FDA has indicated that this study is exempt from needing an IND, in part related to the safety 
of and experience with tocilizumab. Moreover, we have proposed very conservative exclusion criterion to 
ensure that no individuals with any predisposing condition or on any predisposing medication can be 
included in this trial, including exclusion cutoffs of an ANC of 1500 and AST/ALT of 1.5xULN.


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We will now address each of these criterion individually.
 
Regarding platelet counts, the mechanism by which tocilizumab increases platelet counts is not completely 
clear, however, elevated IL-6 levels are thought to stimulate thrombopoietin (Kaser et al., 2001), so 
blocking IL-6 with tocilizumab may mitigate this activity. However, tocilizumab is not a bone marrow 
suppressor and only potentiates thrombopoietin. Therefore, antagonizing IL-6 only leads to a minor 
decrease in platelet counts, if at all, and one that is not related to serious bleeding events and rarely 
decreases below 100K. The frequency of this event is 1-4% in individuals receiving both tocilizumab and 
another DMARD, while in this trial subjects will only be receiving tocilizumab, which is relatively mild 
compared to typical DMARDS (e.g., methotrexate, prednisone). In addition, tocilizumab related decreases 
in platelet counts are not related to serious bleeding events and are readily reversibly after discontinuing 
treatment. In summary, tocilizumab related thrombocytopenia is an extremely uncommon event, is mild 
when it occurs, is fully reversible after discontinuing treatment, and has no substantial clinical relevance.
 
Regarding decreases in neutrophil counts, the mechanism by which tocilizumab decreased neutrophil counts 
is not clear. However, it is thought that IL-6 demarginates neutrophils and accelerates their release from 
marrow (Suwa et al., 2000), so blocking IL-6 would mitigate these effects. In addition, recent data show 
that anti IL6 treatments (such as tocilizumab) do not cause phagocytosis or reduced functioning of 
neutrophils (Wright et al., 2014), confirming these data. Additionally, clinical data from Genentech 
(attached) also show that while Tocilizumab dose decrease ANC, the decrease in ANC has not been 
associated with severe infection. Also, tocilizumab is not a bone marrow suppressor and does not affect the 
overall concentration of neutrophils. Therefore, antagonizing IL-6 only leads to a minor decrease in 
neutrophil counts on laboratory analysis but does not decrease neutrophils overall, and any decrease does 
not lead to serious events. Consistent with this mechanism, agranulocytosis is not considered a risk of 
tocilizumab. In addition, decreases in neutrophil counts are readily reversibly after discontinuing treatment. 
In summary, tocilizumab related neutropenia is an uncommon event, is mild when it occurs, is fully 
reversible after discontinuing treatment, and has no substantial clinical relevance.
 
Regarding transaminitis, tocilizumab is known to irritate the liver, and we expect approximately 33% of 
individuals on tocilizumab (~6 in this trial) to reach up to 3xULN and one percent to reach between 3-5x 
ULN (~0-1 in this trial). However, tocilizumab is not overtly toxic to the liver, and hepatitis or fulminant 
liver failure are not considered risks of tocilizumab. When it occurs, transaminitis is mild, reversible, and 
has no clinical relevance. In summary, tocilizumab related transaminitis is a relatively common event 
though much less common above 3xULN, is mild when it occurs, is fully reversible after discontinuing 
treatment, and has no substantial clinical relevance.
 


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Because of the very low risk of anaphylaxis, as well as fever, chills, nausea, or vomiting due to the 
tocilizumab infusion itself (hypersensitivity reaction), the study physician will have parenteral epinephrine 
and diphenhydramine available during each administration, as well as acetaminophen, and patients will be 
monitored by a study physician or nurse (at the bedside) for one hour after the administration. For the one 
hour time period after the administration, when a nurse is at the bedside of the patient, the study 
physician will be in the immediate proximity (i.e., on 5 South if using 5 South, in the vicinity of the ECT 
suite if using the ECT suite, and in the Division of Translational Imaging if using the Division of Translational 
Imaging, so that, if necessary, the study physician can be at the bedside within 30 seconds). During the one 
hour infusion, the study physician will be present at all times. Patients will also be called by the study 
physician the day after their administration to check in on their status. 
In addition, while we do not expect a change in antipsychotic blood levels during the course of this trial, we 
will be vigilant about monitoring for a change in mental status of all participants in this trial.  
b. These risks are minimized by using proper techniques. In addition, the primary study physician (in most 
cases Dr. Girgis) will assess the IV catheter placement. IV catheters will be removed immediately after 
administration of the study drug is complete (approximately 1 hour after placement).
c. In order to avoid boredom caused by the administration of neuropsychological tests and ratings scales, 
patients will be allowed frequent and regular breaks. If necessary, particularly during the 
screening/baseline visit, patients will be allowed to finish the session on a different day.
d. In order to minimize the risks of loss of confidentiality for those patients who participate in the optional 
audio/videotaping component of this protocol, tapes will be kept in locked drawers, and made available to 
research staff only. Personal identifying information will not be included on the tapes.
 
e. 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. 
 
f. Gadolinium -A trained physician (currently Dr. Girgis) 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 Multihance according to the patient's weight at a dose of 0.1mmol/kg. Based 


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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.
Methods to Protect Confidentiality
Describe methods to protect confidentiality
We use coded records and keep signed consent forms in a locked file cabinet; patients with a positive drug 
screen are not entered in the study. We do, however, point out to prospective subjects that we cannot 
assure that their drug histories and other personal records might not become known.  
Subject names and diagnoses are stored in an electronic database that is accessible only with a password. 
Only the clinical/research staff involved in studies at the Division of Translational Imaging have access to 
the database. Subject names, along with scan information is stored on desktop computers in the division. 
These computers are kept in locked offices. Additionally, personal identifying information is stored in the 
password-protected database at NYSPI (R2Net).
The safety data (e.g., data on adverse events and laboratory values) will be shared with Genentech. All 
correspondences with Genentech will have no more personal identifying information except for a non 
identifying study number. Genentech will not receive any other identifying information.
Will the study be conducted under a certificate of confidentiality?
No
Direct Benefits to Subjects  
Direct Benefits to Subjects
It is possible that subjects who participate in this study will experience an improvement in symptoms. 
However, any such benefits would be expected to be temporary and short-lived.
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.
$50 for each baseline (up to 2), week 2, 12, or 14, which include only assessments.


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$100 for each week 0, 4, 8 visit during which they receive study drug, which will include both assessments 
and study drug administrations.
Compensation schedules are based on time commitment during the respective visits.
$100 for each MRI scan for those individuals who participate in MRI scans. 
 
We will also reimburse for reasonable, local transportation costs.
In total, subjects will receive up to $550 or $700 if they participate in the MRI scans. Compensation will be 
paid by cash or check mailed to the subject’s address 4-6 weeks after the procedure.  If subjects do not 
complete all procedures, payment will be pro-rated for participation.
References
References
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