Clinical trial NCT01779700
Conditions: Schizophrenia
Keywords: psychosis schizophrenia cognition fingolimod
Sponsor: Indiana University
Start date: 2013-01-01; Completion date: 2016-08-01
Enrollment: 40 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This will be a single site safety and proof of concept study conducted at the Indiana University Psychotic Disorders Program. Forty subjects with schizophrenia or schizoaffective disorders will be randomized 1:1 to double-blind treatment with fingolimod or matched placebo for duration of 8 weeks.

Detailed description:
Study Design:

This will be a single site safety and proof of concept study conducted at the Indiana University Psychotic Disorders Program. Forty subjects with schizophrenia or schizoaffective disorders will be randomized 1:1 to double-blind treatment with fingolimod or matched placebo for duration of 8 weeks.

All subjects will be admitted to the Indiana Clinical and Translational Sciences Institute Clinical Research Center (CRC) and remain hospitalized for the first 24 (+/- 2) hours post initial dose of study medication. The CRC is located in Indiana University Hospital and has 24 hour staffing with nurses skilled in conducting Phase 1 and Phase 2 investigational drug studies.

Background and Rationale:

Schizophrenia is a severe brain disorder that begins during the teenage years and early twenties and typically progresses to a life-long chronic illness marked by psychotic symptoms, cognitive impairment and poor functioning. A leading hypothesis to account for the symptoms and cognitive dysfunction of this disorder is that abnormalities exist in cortical circuits, particularly in frontal and temporal areas. An interest in cortical circuitry has led to a focus on the integrity of cortical white matter tracts as possibly contributing to the pathophysiology of this illness. Indeed, several lines of evidence have supported abnormalities in white matter structure and function in schizophrenia. Numerous myelin-related genes and their functional expression have been associated with schizophrenia. Moreover, quantitative and qualitative abnormalities in prefrontal cortical oligodendrocytes have been found in postmortem studies. MRI-determined volumetric reductions in prefrontal white matter have been reported in schizophrenia. Advances in MRI technology have enhanced the ability to study white matter pathology in vivo. Diffusion tensor imaging (DTI) and fractional anisotropy (FA) provides an assessment of the density and integrity of white matter tracts. Decreased FA has been reported in many de-myelinating diseases including multiple sclerosis (MS), leukodystrophies, and HIV. Numerous studies using DTI have reported decrements in FA in schizophrenia with the most consistent abnormalities occurring in frontal cortical white matter. Also, FA has been shown to be sensitive to therapeutic drug effects in MS which supports DTI-derived FA as an outcome measure in clinical trials of neuroprotective agents.

Fingolimod (FTY720, approved as Gilenya™ ) is a sphingosine-1-phosphate (S1P) receptor modulator and recently licensed in the USA and several other countries for relapsing forms of multiple sclerosis (MS). It is administered as a once per day oral preparation. In registration clinical trials, it had positive effects on brain atrophy, MRI-determined axonal lesions and relapse rates. Significant improvement in the mean number of MRI assessed T1 gadolinium (Gd) enhanced lesions/patient and the percentage of patients free of T1 Gd-enhanced lesions was observed within 6 months of treatment and there was evidence of clinical improvement as early as 2 months after treatment initiation

Arms: arm 1: 0.5mg of fingolimod, oral administration, daily, for 8 weeks. arm 2: placebo, oral administration, daily, for 8 weeks.
Interventions: intervention 1: Fingolimod intervention 2: placebo
Intervention descriptions: intervention 1: 0.5mg each day of 8 week cycle intervention 2: 1 tablet each day of 8 week cycle

Protocol documents:
Prot_SAP_000.pdf: 
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Safety and Efficacy of Fingolimod in Schizophrenia Patients 
who have Suboptimal Responses to Antipsychotic Drug 
Treatment    
 
 
 
 
NCT01779700 
 
 
 
 
 
 
 
 
 
Principal Investigator:  
Alan Breier, MD 
Department of Psychiatry 
IU School of Medicine 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table of Contents: 


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Study Schema 
1.0 
Background 
2.0 
Rationale 
3.0 
Specific Aims 
4.0 
Study Design 
5.0 
Study Population (Inclusion/Exclusion Criteria)  
6.0 
Subject Recruitment 
7.0 
Study Procedures 
8.0 
Clinical Assessments and Procedures 
9.0 
Safety Assessments and Procedures 
10.0 Criteria for Repeat Assessments, Rescreening, and 
Discontinuation 
11.0 Laboratory Assessments 
12.0 Study Medication  
13.0 Concomitant Medication 
14.0 Adverse Events 
15.0 Data Safety Monitoring Board  
16.0 Statistical Considerations 
17.0 Privacy/Confidentiality Issues 
18.0 Record Retention 
19.0 References 
 
 
 
 
 


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1.0 
Background 
 
Schizophrenia is a severe brain disorder that begins during the teenage years and early 
twenties and typically progresses to a life-long chronic illness marked by psychotic 
symptoms, cognitive impairment and poor functioning. A leading hypothesis to account 
for the symptoms and cognitive dysfunction of this disorder is that abnormalities exist in 
cortical circuits, particularly in frontal and temporal areas. An interest in cortical circuitry 
has led to a focus on the integrity of cortical white matter tracts as possibly contributing 
to the pathophysiology of this illness. Indeed, several lines of evidence have supported 
abnormalities in white matter structure and function in schizophrenia (1). Numerous 
myelin-related genes and their functional expression have been associated with 
schizophrenia (1, 2). Moreover, quantitative and qualitative abnormalities in prefrontal 
cortical oligodendrocytes have been found in postmortem studies (3, 4). MRI-determined 
volumetric reductions in prefrontal white matter have been reported in schizophrenia (5). 
Advances in MRI technology have enhanced the ability to study white matter pathology 
in vivo. Diffusion tensor imaging (DTI) and fractional anisotropy (FA) provides an 
assessment of the density and integrity of white matter tracts (6). Decreased FA has been 
reported in many de-myelinating diseases including multiple sclerosis (MS), 
leukodystrophies, and HIV (1). Numerous studies using DTI have reported decrements in 
FA in schizophrenia with the most consistent abnormalities occurring in frontal cortical 
white matter (7). Also, FA has been shown to be sensitive to therapeutic drug effects in 
MS which supports DTI-derived FA as an outcome measure in clinical trials of 
neuroprotective agents (8).    
  
The etiopathophysiological mechanisms that have been proposed to account for white 
matter abnormalities in schizophrenia include oxidative stress, altered apoptosis and 
autoimmune mechanisms (9, 10). The possibility that brain abnormalities in 
schizophrenia may be secondary to autoimmune factors has been supported by a large 
literature that includes signs of inflammation and microglia activation in postmortem 
tissue and CSF (11), altered cytokine levels (12) and association of HLA genotypes and 
schizophrenia (13-15). Based on the above literature, agents that increase myelin density 
and integrity through autoimmune mechanisms would be intriguing therapeutic 
candidates to consider for proof of principle trials in schizophrenia.  
 
Fingolimod (FTY720, approved as Gilenya™) is a sphingosine-1-phosphate (S1P) 
receptor modulator and recently licensed in the USA and several other countries for 
relapsing forms of multiple sclerosis (MS). It is administered as a once per day oral 
preparation. In registration clinical trials, it had positive effects on brain atrophy, MRI-
determined axonal lesions and relapse rates (16-18). Significant improvement in the mean 
number of MRI assessed T1 gadolinium (Gd) enhanced lesions/patient and the 
percentage of patients free of T1 Gd-enhanced lesions was observed within 6 months of 
treatment and there was evidence of clinical improvement as early as 2 months after 
treatment initiation (16). In a one year trial, it reduced the number of MS relapses by 
52%. Eighty three percent of patients taking fingolimod remained relapse free compared 
to 70% taking interferon beta-1a, an MS standard of care. In a two year trial, 70% of 
patient taking fingolimod remained relapse free compared to 46% for placebo treated 


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patients. In these studies, there was a significantly lower number of new or enlarged 
white matter lesions compared to interferon beta-1a and placebo (16).   
 
Although not fully understood, fingolimod may have multiple mechanisms by which it 
prevents relapses in MS (19). It is metabolized to fingolimod-phosphate which blocks the 
capacity of lymphocytes to egress from lymph nodes. This results in a reduced number of 
peripherally circulating lymphocytes. It is hypothesized that fingolimod attenuates the 
number of lymphocytes entering the CNS and thereby imparts protection from 
autoimmune-induced neuropathology (20). In addition, there is evidence that fingolimod 
has direct effects on brain tissue. It is highly lipophilic and readily crosses the blood-
brain barrier resulting in substantial CNS concentration with particularly high levels 
found in myelin tissue (20). S1P receptors are located on all brain cell types. S1P 
signaling in oligodendrocytes has been shown to play roles in cell survival (21) and 
proliferation (22). Stimulation of S1P receptor by fingolimod demonstrated 
neuroprotective properties by preserving oligodendrocytes against apoptosis mediated by 
growth factor deprivation and in models of glial-derived oxidative stress (21). In addition, 
fingolimod has been shown to enhance oligodendrocyte precursor cell mitogenesis and to 
produce re-myelination (23, 24). Further, anti-inflammatory properties are supported by 
the decreased gadolinium enhancing lesions found in the clinical trials of MS (16). Thus, 
this compound appears to have multiple actions including immunomodulatory, 
neuroprotective, myelin replenishing and anti-inflammatory properties that may mediate 
its therapeutic effects. Because white matter abnormalities may underlie the 
pathophysiology of schizophrenia and the possibility that these alterations may arise from 
autoimmune and/or oxidative stress mechanisms, we propose to assess the effects of 
fingolimod on measures of white matter density and clinical outcomes in patients with 
schizophrenia.  
 
2.0 
Rationale 
 
Safety of Fingolimod 
To date (May, 2015), more than 36,000 patients have been treated with fingolimod for 
MS. The most serious side effects associated with fingolimod are reduced heart rate, 
atroventricular conduction deficits, risks of infections, posterior reversible 
encephalopathy syndrome, decreased pulmonary function, elevated liver enzymes, fetal 
risk and macular edema.   
 
The most common side effects are headache, liver transaminase elevation, diarrhea, 
cough, influenza, sinusitis, back pain, abdominal pain, and pain in extremity. 
 
In clinical trials following initial dosing, bradycardia occurred commonly and 
symptomatic bradycardia occurred in 0.6% of patient treated with fingolimod and 0.1% 
treated with placebo. In controlled clinical trials, first-degree AV bock after the first dose 
occurred in 4.7% of patients receiving fingolimod and 1.6% of patients on placebo. In a 
study of 697 patients with available 24-hour Holter monitoring data after their first dose 
(N=351 receiving fingolimod and N=346 on placebo), second-degree AV blocks (Mobitz 
Types I [Wenckebach] or 2:1 AV blocks) occurred in 4% (N=14) of patients receiving 


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fingolimod and 2% (N=7) of patients on placebo. Of the 14 patients receiving 
fingolimod, 7 pateints had 2:1 AV block (5 patients within the first 6 hours postdose and 
2 patients after 6 hours postdose). Reduced heart rate is most pronounced six hours after 
the initial dose of fingolimod and normalizes within one month of treatment, though there 
have been cases of delayed cardiac effects.  Because of these cardiac effects, all patients 
are required to remain in the clinic for cardiac monitoring for six hours following the 
initial dose of fingolimod, when used for MS. Concomitant drugs that lower heart rate 
(e.g., beta blockers) are to be avoided and patients with pre-existing cardiac conduction 
deficits may not be appropriate for fingolimod treatment. 
 
Fingolimod also causes a dose-dependent reduction in peripheral lymphocyte count to 
20%-30% of baseline values because of reversible sequestration of lymphocytes in 
lymphoid tissues. Fingolimod may therefore increase the risk of infections, some serious 
in nature.  Additionally, in clinical trials there have been rare cases of posterior reversible 
encephalopathy syndrome (PRES) reported in patients receiving fingolimod. Dyspnea 
was reported in 9% of patients receiving fingolimod 0.5 mg and 7% of patients receiving 
placebo in MS placebo-controlled trials.  Also, in 2-year placebo-controlled clinical trials, 
elevation of liver transaminases to 3-fold the upper limit of normal (ULN) or greater 
occurred in 14% of patients treated with fingolimod 0.5 mg and 3% of patients on 
placebo. Elevations 5-fold the ULN or greater occurred in 4.5% of patients on fingolimod 
and 1% of patients on placebo.  Based on animal studies, fingolimod may cause fetal 
harm.  Fingolimod also increases the risk of macular edema, the risk of which is 
increased in patients with a history of uveitis and patients with diabetes mellitus. In 2-
year, double-blind, placebo-controlled studies in patients with multiple sclerosis, macular 
edema with or without visual symptoms occurred in 1.5% of patients (11/799) treated 
with fingolimod 1.25 mg, 0.5% of patients (4/783) treated with fingolimod 0.5 mg and 
0.4% of patients (3/773) treated with placebo.  
 
Rationale of Study Period 
Two months was chosen as the treatment period because it is an adequate duration for an 
initial safety assessment in schizophrenia of early emerging adverse events. In addition, 
significant effects in MS patients were observed as early as two months post 
randomization (16). Further, Garver et al (25) reported improvement in DTI-determined 
white matter integrity in patients with schizophrenia who responded to antipsychotic drug 
therapy in only 28 days. Thus, if fingolimod has a large effect in improving the 
symptoms of schizophrenia, it may be detected in a two month study of 40 subjects.  
 
3.0 
Specific Aims 
 
The primary aims of this clinical study are to 1) assess the safety of fingolimod in 
subjects with schizophrenia being treated with antipsychotic drugs, and 2) determine if 
fingolimod compared to placebo results in symptomatic improvement as measured by 
reductions in PANSS total score.   
 
 


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Secondary aims include assessment of the effects of fingolimod versus placebo on 
memory, cognition, positive and negative symptoms, and  plasma cytokine levels in 
addition to gathering preliminary data on the effects of fingolimod on DTI-derived FA 
and other MRI indices. 
 
4.0  
Study Design  
 
This will be a single site safety and proof of concept study conducted at the Indiana 
University Psychotic Disorders Program. Forty subjects with schizophrenia or 
schizoaffective disorders with suboptimally treated symptoms (despite previous and/or 
current antipsychotic medication exposure) (39) will be randomized 1:1 to double-blind 
treatment with fingolimod or matched placebo for duration of 8 weeks.  
 
All subjects will be admitted to the Indiana Clinical and Translational Sciences Institute 
Clinical Research Center (CRC) and remain hospitalized for the first 24 (+/- 2) hours post 
initial dose of study medication. The CRC is located in Indiana University Hospital and 
has 24 hour staffing with nurses skilled in conducting Phase 1 and Phase 2 investigational 
drug studies. 
 
5.0 
Study Population (Inclusion/Exclusion Criteria) 
 
Inclusion criteria: 
1. 18 to 65 years of age at study entry 
2. Male or female 
3. DSM IV-TR Diagnosis of schizophrenia or schizoaffective disorder as confirmed 
by Structured Clinical Interview for DSM-IV-TR (SCID) 
4. Previous and/or current exposure to one of the following antipsychotic 
medication (clozapine, olanzapine, risperidone, paliperidone, haloperidol, and 
quetiapine) as defined by a minimum of 8 weeks in duration greater than or equal 
to the Food and Drug Administration approved therapeutic range for 
schizophrenia at time of study entry OR previous and/or current exposure 
to two antipsychotic medications as defined by a minimum of 4 weeks in duration 
greater than or equal to the Food and Drug Administration approved therapeutic 
range for schizophrenia at time of study entry 
5. Able to give informed consent (or has an active guardian or LAR who is willing 
to consent on behalf of the subject) 
6. Subjects must be willing to participate in a minimum of 1 day of inpatient 
hospitalization 
7. Inpatient or outpatient 
8. Clinical stability as defined by:  
a. CGI-S score of less than or equal to 4 (moderately ill) at randomization 
AND 
b. Subjects must not have experienced an exacerbation of their illness within 
4 weeks prior to randomization, leading to an intensification of psychiatric 
care in the opinion of the investigator. Examples of intensification of care 


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include, but are not limited to: inpatient hospitalization, day/partial 
hospitalization, outpatient crisis management, or psychiatric treatment in 
an emergency room AND 
c. Antipsychotic treatment stability for at least 4 weeks prior to 
randomization (no change in antipsychotic dosing or addition of any new 
antipsychotic medication) 
9. Female subjects of childbearing potential must test negative for pregnancy at 
screening visit and agree to use a single, effective, medically acceptable method 
of birth control for the duration of the study and for two months following 
cessation of study medication 
10. Subjects must agree not to consume tonic water for the duration of the study and 
for two months following cessation of study medication.  
11. Sub-optimally treated positive symptoms OR negative symptoms at the time of 
study entry as defined by the Brief Psychiatric Rating Scale (BPRS):  
a. BPRS positive symptom factor (conceptual disorganization, 
hallucinations, suspiciousness, and unusual thought content) score of 
greater than or equal to 4 on any one item or a sum greater than or equal to 
8 on the factor.  
b. BPRS negative symptom factor (motor retardation, blunted affect, and 
inappropriate affect) score of greater than or equal to 4 on any one item or 
a sum greater than or equal to 6 on the factor.  
 
Exclusion criteria: 
1. Subjects who are considered prisoners per the Indiana University Standard 
Operating Procedures for Research Involving Human Subjects. 
2. Subjects with current acute, serious, or unstable medical conditions, including, but 
not limited to: inadequately controlled diabetes, asthma, COPD, severe 
hypertriglyceridemia, recent cerebrovascular accidents, acute systemic infection 
or immunologic disease, unstable cardiovascular disorders, malnutrition, or 
hepatic, renal gastroenterologic, respiratory, endocrinologic, neurologic, 
hematologic, or infectious diseases 
3. Clinically significant electrocardiogram (ECG) abnormality prior to 
randomization as defined by: subjects with a corrected QT interval (Bazett’s; 
QTcB) >450 msec (male) or >470 msec (female) prior to randomization (based on 
the cardiologist overread) OR sinus bradycardia (resting heart rate < 50 beats per 
min). Repeat ECGs will be conducted at the discretion of the principal 
investigator or medical designee 
4. Subjects with hypokalemia, hypomagnesemia, or congenital long-QT syndrome 
5. Subjects with known medical history of Human Immunodeficiency Virus positive 
(HIV+) status or tuberculosis  
6. Subjects with an active seizure disorder  
7. Pregnant or lactating women or women who plan to become pregnant or will be 
lactating within two months after cessation of study drug 
8. Implanted pacemaker, medication pump, vagal stimulator, deep brain stimulator, 
TENS unit, ventriculoperitoneal shunt, or other contraindication to undergoing an 
MRI scan..  


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9. Subjects taking class1a or class 3 antiarrhythmic agents, beta blockers, diltiazem, 
verapamil, digoxin, tricyclic antidepressants, warfarin, ketoconazole, ketamine. 
10. Subjects who will be likely to need a live attenuated vaccine during the course of 
the study or within two months after stopping study medication 
11. Subjects with no history of chicken pox or chicken pox vaccination, or with a 
negative VZV titer 
12. Active herpes simplex outbreak, mononucleosis, or zoster. 
13. Subjects with histories of ischemic heart disease, myocardial infarction, 
congestive heart failure, cardiac arrest, cerebrovascular disease, unexplained or 
recurrent syncope, cardiac conduction prolongations (prolonged P-R interval), 
cardiac arrhythmias, symptomatic bradycardia, decompensated heart failure 
requiring hospitalization or Class III/IV heart failure, or severe untreated sleep 
apnea 
14. Subjects receiving antineoplastic, immunosuppressive, or immune modulating 
therapies 
15. Subjects with history of macular edema or uveitis based on medical history  
16. Known IQ less than 70 based on medical history 
17. Subjects with current active fungal or viral infection based on history and physical 
examination 
18. Current DSM IV-TR diagnosis of substance dependence (excluding caffeine and 
nicotine)  
19. Positive urine toxicology screen for the following: cocaine, barbiturates, 
methamphetamine, opiate, methadone, phencyclidine, or amphetamine prior to 
randomization 
20. Test positive for (1) Hepatitis C virus antibody, (2) Hepatitis B surface antigen 
(HBsAg) with or without positive Hepatitis B core total antibody, or (3) HIV 1 or 
2 antibodies  
21. Subjects with moderate to severe renal impairment as defined by creatinine 
clearance (CrCl) < 60 ml/min (measured by the Cockcroft-Gault equation) at 
screening 
22. Subjects with hepatic impairment as defined by liver transaminases or total 
bilirubin > 3 × upper limit of normal (ULN) 
23. Subjects considered a high risk for suicidal acts – active suicidal ideation as 
determined by clinical interview OR any suicide attempt in 90 days prior to 
screening  
24. Subjects who have participated in a clinical trial with any pharmacological 
treatment intervention for which they received study-related medication in the 4 
weeks prior to screening OR Subjects currently receiving treatment (within 1 
dosing interval plus 4 weeks) with an investigational depot formulation of an 
antipsychotic medication 
25. Subjects who demonstrate overtly aggressive behavior or who are deemed to pose 
a homicidal risk in the investigator’s opinion 
 
 
 
 
 


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6.0 
Subject Recruitment 
 
Subjects will be recruited through referring community mental health centers, treatment 
providers, invited to participate if they are included in our registry, and self-referrals 
through advertisement and word-of-mouth.  
 
7.0 
Study Procedures 
 
See Study Procedures Table Attachment 1  
 
8.0 
Clinical Assessments and Procedures 
 
The following assessments will be administered at one or more visits during the duration 
of the study according to the study procedures tables (Attachment 1). All assessments 
will be completed by study personnel based on interviews with the subject or based on 
questionnaires completed by the subject (i.e. EuroQol).  
 
Diagnostic Interview 
The Structured Clinical Interview for DSM-IV-TR (SCID-I/P Patient Edition) will be 
used to confirm the diagnosis of a psychotic disorder and/or rule out other diagnoses. The 
SCID-IP is a semi-structured interview designed to evaluate DSM-IV-TR Axis I 
diagnoses.  
 
The Brief Psychiatric Rating Scale (BPRS) 
The BPRS is an 18-item scale measuring positive symptoms, general psychopathology 
and affective symptoms (38). Some of the items (eg mannerisms and posturing) can be 
rated simply on observation of the subject; other items (eg anxiety) involve an element of 
self-reporting by the subject. 
 
Clinical Global Impressions Severity Scale (CGI-S)  
The CGI-S will be used for repeated evaluations of global psychopathology (34-35). The 
CGI-S scale is widely used in schizophrenia research and is a single 7-point Likert scale 
rating severity of psychopathology on a scale of 1 (normal, not ill) to 7 (very severely ill). 
 
Clinical Global Impressions Severity Improvement Scale (CGI-I)  
The CGI-I is used to assess the clinical change as compared to symptoms at baseline 
using a 7-point Likert scale, ranging from very much improved (1) to very much worse 
(7) (34-35). 
 
The Positive and Negative Syndrome Scale (PANSS)  
The PANSS will be the primary assessment instrument for psychopathology (27). The 
PANSS contains 30 items that assess symptoms of psychotic disorders including positive, 
negative and general psychopathology. The PANSS was chosen because of its 
widespread use in clinical studies of psychosis, and its demonstrated reliability in 
assessing psychopathology across diverse patient populations.  
 
 


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Personal and Social Performance Scale (PSP)  
The PSP scale (32) is a 100-point, single item, clinician rated scale to assess 4 domains of 
functioning, including personal and social relationships, socially useful activities, self-
care and disturbing and aggressive behaviors.  
 
EuroQol Questionaire-5 dimensions (EQ-5D) 
The EQ-5D (30) is a generic, multidimensional, health-related, quality-of-life instrument 
that contains two parts: a health status profile, and a visual analog scale to rate global 
health-related quality of life. 
 
Quality of Life Scale (QLS) 
Quality of Life Scale (QLS), a 21-item scale based on a semistructured interview 
designed to assess deficit symptoms. 
 
Abnormal Involuntary Movement Scale (AIMS) 
The AIMS is a 12-item scale designed to records the occurrence of dyskinetic movements 
(29). Items 1 to 10 are rated on a 5-point scale, with 0 being no dyskinetic movements 
and 4 being severe dyskinetic movements. Items 11 and 12 are yes/no questions 
regarding the dental condition of as subject.  
 
Barnes Akathisia Scale (BARS)  
The BARS is used to rate drug-induced akathisia (31). Symptoms are rated on a 4-point 
scale, with 0 being no akathisia and 3 being severe akathisia. A global clinical assessment 
of akathisia is then scored on a 6-point scale, with 0 being no evidence of akathisia and 5 
being severe akathisia. 
 
Simpson Angus Scale (SAS) 
The SAS is a 10-item scale used to evaluate the presence and severity of drug induced 
Parkinsonism (33). Each item is rated from 0 to 4. 
 
Busch Francis Catatonia Rating Scale (BFCRS) Evaluation 
The BFCRS consists of 23 sections supplemented by specific instructions to standardize 
the evaluation (26). Seventeen sections are scored on a 0 to 3 scale while the last 6 
sections are rated as either absent (“0”) or present (“3”). The total score ranges from 0 to 
69.  
 
Brief Assessment of Cognition in Schizophrenia (BACS)  
The BACS (Keefe et al, 2004) is a battery specifically designed to measure treatment-
related changes in cognition, and has alternate forms, thus minimizing practice effects. 
The battery includes brief assessments of executive functions, verbal fluency, attention, 
verbal memory, working memory and motor speed, and generates a composite score that 
is calculated by summing z-scores derived by comparisons with a normative sample of 
400 healthy controls. The reliability, validity and comparability of forms has been 
established empirically (Keefe et al, 2004). The composite score have high test–retest 
reliability in people with schizophrenia and healthy controls (intraclass correlation 
coefficients>0.80).  


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Trail Making Test-Part B 
The Trail Making Test is a neuropsychological test of visual attention and task switching 
(28). The subject is instructed to connect a set of 25 dots as fast as possible while still 
maintaining accuracy. The test provides information about visual search speed, scanning, 
speed of processing, mental flexibility, as well as executive functioning and sensitive to 
detecting several cognitive impairments. The task requires a subject to 'connect-the-dots' 
of 25 consecutive targets on a sheet of paper. In Part B version the subject alternates 
between numbers and letters (1, A, 2, B, etc.) The goal of the test is for the subject is to 
finish part B as quickly as possible, the time taken to complete the test is used as the 
primary performance metric. Error rate is not recorded in the paper and pencil version of 
the test, however, it is assumed that if errors are made it will be reflected in the 
completion time.  
 
Magnetic Resonance (MR) Measures 
The MR work of this project will be conducted at Indiana University Center for 
Neuroimaging. A Siemens 3T Trio MR system equipped with a novel 32-channel head 
coil will be used. This study will use an MR imaging protocol optimized for 3T to 
provide optimal contrast between grey matter, white matter and CSF. The MR imaging 
protocol is designed to assess brain changes that may be associated with both white 
matter and grey matter as well as functional changes associated with duration of illness. 
Subjects will receive a high-resolution, isotropic 1 mm3 T1-weighted gradient echo MRI 
(MPRAGE) for brain segmentation into gray matter, white matter and cerebrospinal fluid 
(CSF) and for highly sensitive visualization of T1-signal changes in the brain due to Mn 
deposition. The diffusion tensor images are collected with a 2mm isotropic resolution to 
study white matter changes.  Functional images will be acquired with T2*-weighted 
gradient echo-planar imaging (EPI) scans with a resolution of 2.5x2.5x3.5mm to assess 
brain activity during resting state and task paradigms. Quantitative measurement of 
cortical thickness and potential atrophy using automated Freesurfer and VBM 
parcellation methods will be conducted, as well as fronto-temporal axonal tract integrity 
(cingulum, arcuate and uncinate fasciculi) assessed by DTI tractography; and cortical 
activation with fMRI coupled with working and semantic memory tasks. 
  
The MRI scanning procedure will last approximately 60 minutes and follows the order 
described below: 
1. Written informed consent and MRI Safety Screening will be obtained and documented. 
2. Prior to MRI scanning, female subjects who have begun to menstruate and have not 
undergone menopause or a hysterectomy will take a urine pregnancy test. The 
pregnancy test will be administered by research staff and there will be no charge to 
the subject. Subjects who are found to be pregnant will be informed 
3. Prior to scanning all subjects will first empty their bladder and remove any metal objects 
or if required, change into a hospital gown. 
4. Subjects will be placed in supine on the scanner table. All scans will be completed in the 
Siemens Magnetom Trio 3.0T magnet 
5. As needed for a particular scan sequence, noninvasive physiological monitoring devices 
will be put in place, potentially including: pulse oximeter and respiratory bellows. 


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Artifact due to cardiac and respiratory factors can be a problem for MRI and information 
on these sources can be used to minimize and correct for them. 
6. Peripheral audio devices will be put in place, including ear plugs and sound dampening 
headphones, to enable the subject to hear auditory instructions and protect hearing against 
scanner noise, and goggles to allow subjects to see stimuli for visual fMRI tasks. 
7. The RF imaging coil will be slid down over the subject’s head and the scanner table will 
be inserted into the bore of the magnet such that the head is at the geometric center of the 
magnet tube. 
8. Preliminary scout images will be obtained to evaluate head position. High resolution 
anatomic images may be acquired with which to co-register the sequences being tested 
(e.g., MPRAGE, T1, PD/T2, B0, or FLAIR images), and to use for radiological review of 
any incidental or known structural abnormalities. 
9. Depending upon the sequences/tasks to be evaluated, other MR scans will be obtained, 
potentially to include fMRI, DTI, and ASL series. Any changes made to a sequence, 
including self-programmed sequences, will fulfill the safety limitations of the Siemens 
Scanner (e.g., limitations on power deposition). 
10. fMRI stimulation paradigms may include tasks of memory, language, attention and 
executive functions, affect, and/or sensorimotor processing (i.e., visual, olfactory, 
gustatory, auditory, or tactile stimuli). 
11. Subjects will be removed from the scanner following imaging. 
 
9.0 
Safety Assessments and Procedures 
 
Dosing Safety 
 
First dose monitoring 
• The first dose of study medication will be administered at the CRC  
• All subjects will be placed on continuous telemetry during the first 24 (+/- 2) hours 
following administration of the first dose of study medication 
• Blood pressure measurements will be completed hourly during the first 6 hours post 
initial dose of study medication and every 4 (+/- 1) hours thereafter unless study 
doctor determines a different schedule based on safety. 
 
Second dose monitoring  
• For subjects who require pharmacologic intervention for symptomatic bradycardia at 
any time within the first 24 (+/-2) hours, whose electrocardiogram shows new onset 
second degree or higher AV block at any time within the first 24 (+/-2) hours or who 
continue to have bradycardia (resting heart rate < 50 beats per min) after 24 (+/- 2) 
hours (with or without pharmacologic intervention), first dose monitoring procedures 
will be reinstituted following the second dose 
 
Ophthalmologic Examination 
Ophthalmologic examination will be performed before initiating study medication and at 
4 (+/-1) months after treatment initiation. For subjects who report visual changes, an 
additional examination will be completed 


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Vitals 
Vital signs will be assessed at study visits per Study Procedures Table (Attachment 1).  
Blood pressure, heart rate, and oxygen saturation will be taken in a seated position after a 
rest period of five minutes.  Oxygen saturation will be taken via a finger mounted pulse 
oximeter.   
 
Medical History 
The subject’s lifetime medical history will be taken during the screening period. Medical 
history includes previous and current diseases.  
 
Physical Examination  
A physical examination including a neurological examination.  
 
Electrocardiograph (ECG) 
A supine, 12 lead ECG will be performed according to the Study Procedures Table 
(Attachment 1). ECGs will be interpreted by a local cardiologist.  
 
Telemetry 
Cardiac telemetry, monitoring of the cardiac rhythm and transmission of signals or data 
from one electronic unit to another by radio waves using a device that provides real-time 
measurement of a subject’s ECG for various lengths of time, will be performed according 
to the Study Procedures Table (Attachment 1). Subjects will be outfitted with measuring, 
recording, and transmitting devices. An alerting function will alert CRC staff if the 
subject is suffering from an acute condition. 
 
Other Safety Assessments 
• Unexplained dyspnea has been reported in clinical trials of this study medication; 
therefore, subjects who develop unexplained dyspnea during the study will 
complete an assessment of pulmonary function (spirometric testing) and 
assessment of diffusion lung capacity for carbon monoxide (DLCO). 
• Subjects will be assessed for active infectious disease by clinical history (and 
physical exam, if necessary) at each study visit. 
• Liver enzymes will be monitored at baseline (Visit 1), 4 weeks (Visit 7), and 8 
weeks (Visit 11) as well as at the two month follow up visit (Visit 13) and in 
subjects who develop signs or symptoms of liver dysfunction including 
unexplained nausea and/or vomiting, abdominal pain, fatigue, anorexia, jaundice, 
and/or dark urine. 
 
10.0 Criteria for Rescreening, Repeat Assessments, and 
Discontinuation 
 
Repeat Assessments 
Screening assessments can be repeated within the screening window under the same 
screening number with the exception of eligibility criteria related rating 
scales/questionnaires. Subject diagnosis confirmation will not be repeated.  


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Rescreening 
Subject who screen fail may be rescreened one time, under a new screening number. If a 
subject is rescreened, all screening assessments (with the exception of the diagnosis 
confirmation) must be repeated and the stability criteria timelines must be met.  
 
Discontinuation  
Subjects will be discontinued under the following circumstances: 
1. Within the first two weeks of treatment, subjects with an interruption of treatment 
of one day or more 
2. Within the third and fourth week of treatment, subjects with an interruption of 
treatment of more than seven days 
3. Subjects who have an elevation of liver transaminase levels >3 times the ULN 
while on study medication 
4. Subjects who develop moderate or severe renal impairment as defined by CrCl 
<60 ml/min (measured by the Cockcroft-Gault equation) while on study 
medication 
5. Female subjects who become pregnant while on study medication 
6. Subjects who develop a serious infectious disease while on study medication 
7. Subjects who develop macular edema or uveitis while on study medication 
8. Any subject who requires pharmacologic intervention for symptomatic 
bradycardia after the second dose of study medication or who continues to 
experience bradycardia or who demonstrates any other new, serious cardiac 
pathology 24 (+/-2) hours after the second dose of study medication will be 
discontinued from the study 
9. Subjects who require an increase in their dose of antipsychotic medication or the 
addition of a new antipsychotic medication 
10. Subjects who require treatment with any excluded concomitant medications (See 
Attachment 2) 
 
If subjects discontinue from the study, discontinuation assessments will be at the 
discretion of the principal investigator. 
 
A subject may withdraw from the study medication at any time at his/her own request, or 
may be withdrawn at any time at the discretion of the principal investigator for safety, 
behavioral, or administrative reasons.  
 
11.0 Laboratory Assessments 
 
Study associated laboratory assessments (blood and urine) will be collected at time points 
specified in Study Procedures Table (Attachment 1) and analyzed by a local laboratory 
with the exception of the urine dipstick assessments which will be collected and analyzed 
onsite.  
 
A total of 36 mL of blood will be collected for baseline/screening assessments (Visit 1) 
and 30 mL of blood (at each visit) will be collected at weeks 4 and 8 (Visits 7 and 11).  


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Laboratory assessments to be completed:  
complete blood count with differential (CBC w/diff) 
comprehensive metabolic panel (CMP) 
magnesium 
calcium 
lipid panel 
hemoglobin A1c (HgbA1c) 
thyroid stimulating hormone level (TSH) 
pregnancy test (serum (beta HCG) and urine) 
varicella zoster titer (VZV titer) 
urine toxicology screen 
HIV test 
hepatitis panel 
plasma cytokines  
 
Plasma cytokines 
Research staff members will transport the cytokine specimens to Indiana Clinical and 
Translational Sciences Institute (CTSI) for processing and storage. Specimen handling procedures 
will be performed based on the CTSI standard operating procedures.  
 
Assay Methodology: 
Plasma cytokine and soluble receptor quantifications will be performed in duplicates using pre-
validated commercially available assay kits employing Luminex® x-MAP technology. With this 
approach, we will be able to simultaneously quantify multiple human cytokines of relevance in a 
single experiment using very small volume of sample (Less than 50-µl). Each of the assay kits 
employs 1-2 positive control(s) of known concentration and a negative control in every run.  We 
will follow manufacturer provided established protocols for these assays. The testing panel for 
cytokines include IFN-γ, IL-10, IL-12p40,IL-12p70, IL-17, IL-1β, IL-1ra, IL-2, IL-4, IL-6, and 
TNF-α (Millipore #HCYTOMAG-60K) and the testing panel for soluble receptors include 
soluble IL-2Rα, soluble IL-6R, soluble TNFRI and soluble TNFRII (Millipore HSCR-32K-04).   
Luminex® is an antibody-based fluorescent immunoassay performed in suspension using 
distinctly identifiable bead sets. This platform uses internally color-coded microspheres (up to 
100 distinct bead sets are available), for coating with a capture antibody specific for a target 
cytokine. The capability of adding multiple conjugated beads to each sample results in the ability 
to obtain multiple results from each sample. After the target cytokine from a test sample is 
captured by the bead, a biotinylated detection antibody is introduced. The reaction mixture is then 
incubated with Streptavidin-Phycoerythrin conjugate, the reporter molecule, to complete the 
reaction on the surface of each microsphere. The microspheres are allowed to pass rapidly 
through a laser which excites the internal dyes marking the microsphere set. A second laser 
excites PE, the fluorescent dye on the reporter molecule. Finally, high-speed digital-signal 
processors in the special reader instrument (Bio-Plex 200 system from Bio-Rad) identify each 
individual microsphere and quantify the result of its bioassay based on fluorescent reporter 
signals. A cytokine standard mix containing all target cytokines at known calibrated levels will be 
used to generate separate standard curves for each of the cytokines. Concentrations of each target 
cytokine will then be estimated using a standard curve specific to that particular cytokine by 5-
parameter logistic curve fit method.  
 
 


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Preservation and Specimen Storage:  
At the time of specimen submission to and processing by the CTSI the specimens will be stored 
in the freezers in specially labeled boxes, organized by internal “grids” for easy tracking.  The 
bar-coded ID number and location of each specimen in the freezer will be entered and tracked by 
the CaTissue specimen database, a CTSI-maintained, password-protected database with limited 
access.  No personal identifiers will appear on the blood tubes stored at the CTSI. The CTSI 
freezers will be secured and wired to an alarm system. The daily monitoring and maintenance of 
the freezers will be managed by the CTSI.  
 
All study information will be stored in locked file cabinets and in password-protected computer 
files. Specimens will be stored by the Indiana CTSI on the IU campus but are not the property of 
the Indiana CTSI.  The PI and IU will remain responsible for the specimens.  
 
All specimens will be kept until they are used in their entirety.  
 
12.0 Study Medication 
 
Fingolimod (FTY720, approved as Gilenya™) a sphingosine-1-phosphate (S1P) receptor 
modulator and matching placebo tablets will be used as study medication for this study. 
Placebo tablets will look like fingolimod tablets, with matching shape, taste, and color. 
Study medication will be purchased directly through the Wishard pharmacy. Wishard 
pharmacists will over-encapsulate the fingolimod and create matching placebo capsules.  
Study medication will be stored according to the details on the product label.  
 
Dosing 
The dosing used in this study will follow doses recommended for MS which is 0.5 mg by 
mouth once daily (see package insert for more information).  
 
Compliance 
Compliance will be assessed at each visit by direct questioning and medication count of 
unused medication and packaging to be returned at each visit. Adequate study medication 
dispensing records will be obtained.  
 
13.0 Concomitant Medication 
See Concomitant Medication Table Attachment 2  
 
14.0 Adverse Events 
 
Adverse events (AEs), especially those for which the relationship to study medication is 
not “unrelated,” will be followed up until they have returned to baseline status or 
stabilized at the discretion of the principal investigator. If after the follow-up period, 
return to baseline or stabilization cannot be established an explanation will be recorded in 
the source documentation.  
 
 
 


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15.0 Data Safety Monitoring Board 
 
The Indiana University Adult Psychiatry Data Safety Monitoring Board (DSMB) will be 
responsible for data and safety monitoring. DSMB is responsible for reviewing study 
procedures, adverse events, safety mailings (if applicable), enrollment, active subjects, 
and ongoing conduct of the research. The DSMB members can ask questions and make 
comments and/or recommendations. The IRB is notified of significant findings by way of 
the DSMB meeting minutes at the time of continuing review. For a list of current DSMB 
members, see Psychiatry DSMB Board Members supplement. An updated DSMB 
member list will be provided at the time of Institutional Review Board (IRB) continuing 
review or upon request.  
 
Due to the small sample size and single site design of this protocol, there is not sufficient 
justification for conducting interim analyses to examine trends.  
 
Data on the number of subjects enrolled and the number of adverse events will be 
reviewed by the Board at least quarterly and more frequently if needed. The resultant 
report will be issued to the Indiana University IRB at least at the time of continuing 
review or more frequently by request.  
 
Any unanticipated events will be immediately directed to the principal investigator who 
will follow the Indiana University IRB reporting procedures.  
 
16.0 Statistical Considerations 
 
Analyses 
In terms of the power to detect a significant effect of this molecule, there are no known 
calculations with schizophrenia patients. However, an extension phase of a MS 
registration trial found that patients on fingolimod demonstrated rapid anti-inflammatory 
responses in relatively small samples (< 35 subjects per dosing arm) (16). In addition, 
Garver et al (25) examined myelin integrity in schizophrenia and found significant 
improvement in white matter integrity utilizing a small sample (N=8) of antipsychotic 
drug responsive schizophrenic patients. Given the above findings, it is reasonable to 
assume a medium (0.50) to large effect size (0.80) will be observed. Therefore, with a 
sample size of 40 patients, we could detect a significant effect of treatment (between the 
fingolimod and placebo groups) with statistical power (37) between .3 and .7, utilizing a 
two-sided independent test and a significance level of 0.05. 
 
Preliminary analyses will consist of descriptive statistics for all outcome variables, 
including summary statistics, graphical displays of distributions, and spaghetti plots of 
individual data over time to detect possible data errors. Demographic and clinical 
characteristics at baseline will be compared between the two randomized groups, using 
parametric or nonparametric test statistics as appropriate. Variables that show significant 
differences will be added to the final models as covariates in order to ensure that the 
observed treatment effects are not spurious or due to demographic confounds. Data 


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Page 18 of 24 
analysis will be intent to treat with all data considered usable providing subjects have 
completed the randomization visit. To minimize the potential for Type I error, all 
treatment comparisons will be evaluated based on a two-sided significance level of 0.05. 
Primary and secondary measures will be examined using ANOVA and ANCOVA 
general linear modeling analyses for measures resulting in ratio data or the Kruskal-
Wallis for those measures that produce ordinal data. 
 
17.0 Privacy/Confidentiality Issues 
 
Confidentiality will be protected by ensuring all research staff have been properly trained 
in confidentiality and human subject research procedures, coding all subject information 
when possible, and by securing subject files in a locked filing cabinet or on secured 
databases with access available only to the principal investigator and research staff. 
Furthermore, data entered into a computer database will only use subject codes on 
secured computers that will be password protected with access available only to the 
principal investigator and research staff. Any screening information obtained from 
potential research subjects who subsequently do not participate in the research study will 
be destroyed. 
 
18.0 Record Retention 
 
Paper copies of medical records and source documentation will be kept for seven years 
after the study is closed with the IRB. One year after study closure, the documents will be 
shipped to the Indiana University Department of Psychiatry long-term storage facility 
until destruction. 
 
19.0 References 
 
1. Davis KL, Stewart DG, Friedman JI, Buchsbaum M, Harvey PD, Hof PR, et al. White 
matter changes in schizophrenia: evidence for myelin-related dysfunction. 
Archives of General Psychiatry 2003; 60 (5):443–56. 
2. Hakak Y, Walker JR, Li C, Wong WH, Davis KL, Buxbaum JD, et al. Genome-wide 
expression analysis reveals dysregulation of myelination-related genes in chronic 
schizophrenia. Proceedings of the National Academy of Sciences of United States 
America 2001;98(8):4746–51. 
3. Uranova N, Orlovskaya D, Vikhreva O, Zimina I, Kolomeets N, Vostrikov V, et al. 
Electron microscopy of oligodendroglia in severe mental illness. Brain Research 
Bulletin 2001;55(5):597–610. 
4. Uranova NA, Vostrikov VM, Orlovskaya DD, Rachmanova VI. Oligodendroglial 
density in the prefrontal cortex in schizophrenia and mood disorders: a study from 
the Stanley Neuropathology Consortium. Schizophrenia Research 2004;67(2–
3):269–75. 
5. Breier A, Buchanan RW, Elkashef A, Munson RC, Kirkpatrick B, Gellad F. Brain 
morphology and schizophrenia. A magnetic resonance imaging study of limbic, 
prefrontal cortex, and caudate structures. Archives of General Psychiatry 1992;49 
(12):921–6 


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6. Basser PJ. Inferring microstructural features and the physiological state of tissues from 
diffusion-weighted images. NMR in Biomedicine 1995;8(7–8):333–44. 
7. Kubicki et al A review of diffusion tensor imaging studies in schizophrenia Journal of 
Psychiatric Research 41 (2007) 15–30. 
8. Fox RJ, Cronin T, Lin J, et al Measuring myelin repair and axonal loss with diffusion 
tensor imaging. Am J Neuroradiol. 2011; 32: 85-91. 
9. Brown AS, Susser ES (2002): In utero infection and adult schizophrenia. Ment Retard 
Dev Disabil Res Rev 8:51–57. 
10. Eaton WW, Byrne M, Ewald H, Mors O, Chen CY, Agerbo E, et al. (2006): 
Association of schizophrenia and autoimmune diseases: Linkage of Danish 
national registers. Am J Psychiatry 163:521–528. 
11. Monji A, Kato T, Kanaba S (2009): Cytokines and schizophrenia: Microglia 
hypothesis of schizophrenia. Psychiatry and Clinical Neuroscience 63: 257-265. 
12. Potvin et al Review of cytokine levels in schizophrenia Biol Psychiatry 2008;63:801–
808 
13. International Schizophrenia Consortium, Purcell SM, Wray NR, Stone JL, Visscher 
PM, O’Donovan MC, et al. Common polygenic variation contributes to risk of 
schizophrenia and bipolar disorder. Nature 2009;460:748e52. 
14. Shi J, Levinson DF, Duan J, Sanders AR, Zheng Y, Pe’er I, et al. Common variants 
on chromosome 6p22.1 are associated with schizophrenia. Nature 
2009;460:753e7. 
15. Stefansson H, Ophoff RA, Steinberg S, Andreassen OA, Cichon S, Rujescu D, et al. 
Common variants conferring risk of schizophrenia. Nature 2009;460:744e7. 
16. Kappos L, Antel J, Comi G, Montalban X, O’Connor P, Polman CH, Haas T, Korn 
AA, Karlsson G, Radue EW: Oral fingolimod (FTY720) for relapsing multiple 
sclerosis. N Engl J Med 2006, 355(11):1124-1140. 
17. Kappos L, Radue E-W, O’Connor P, et al. A placebo controlled trial of oral 
fingolimod in relapsing multiple sclerosis. N Engl J Med 2010; 362 (5): 387-401 
18. Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for 
relapsing multiple sclerosis. N Engl J Med 2010; 362 (5): 402-15. 
19. Jackson et al Fingolimod modulates microglial activation to augment markers of 
remyelination J Neuroinflammation. 2011; 8: 76.17. Chun J, Hartung H-P. 
Mechanism of action of oral fingolimod (FTY720) in multiple sclerosis. Clin 
Neuropharmacol 2010; 33 (2): 91-101. 
20. Foster CA, Howard LM, Schweitzer A, Persohn E, Hiestand PC, Balatoni B, 
Reuschel R, Beerli C, Schwartz M, Billich A. Brain penetration of the oral 
immunomodulatory drug FTY720 and its phosphorylation in the central nervous 
system during experimental autoimmune encephalomyelitis: consequences for 
mode of action in multiple sclerosis. J Pharmacol Exp Ther. 2007; 323(2):469–
475. 
21. Coelho RP, Payne SG, Bittman R, Spiegel S, Sato-Bigbee C. The immunomodulator 
FTY720 has a direct cytoprotective effect in oligodendrocyte progenitors. J 
Pharmacol Exp Ther. 2007;323(2):626–635. 
22. Jung CG, Kim HJ, Miron VE, Cook S, Kennedy TE, Foster CA, Antel JP, Soliven B. 
Functional consequences of S1P receptor modulation in rat oligodendroglial 
lineage cells. Glia. 2007;55 (16):1656–1667.  


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23. Miron VE, Ludwin SK, Darlington PJ, Jarjour AA, Soliven B, Kennedy TE, Antel JP: 
Fingolimod (FTY720) enhances remyelination following demyelination of 
organotypic cerebellar slices. Am J Pathol 2010, 176(6):2682-2694. 
24. Miron, V.E. et al. (2008) FTY720 modulates human oligodendrocyte progenitor 
process extension and survival. Ann. Neurol. 63, 61–71. 
25. Garver DL, Holcomb J, Christensen JD. Compromised myelin integrity during 
psychosis with repair during remission in drug responding schizophrenia.  
International Journal of Neuropsychopharmacology (2008), 11, 49–61.  
26. Busch G, Fink M, Petrides G, Dowling F, Frances A. Catatonia. Rating scale and 
standardized examination. Acta Psychiatr Scand 1996;93:129–143. 
27. Kay, SR, Fizbein A, Opler LA. The Positive and Negative Syndrome Scale (PANSS) 
for schizophrenia. Schizophrenia Bulletin. 1987;13:261-76. 
28. Reitan, R. M. (1955f). The relation of the Trail Making Test to organic brain damage. 
Journal of General Psychology, 53, 97-107. 
29. Psychopharmacology Research Branch. U.S. Department of Health, Education, and 
Welfare: Abnormal Involuntary Movement Scale. Early Clinical Drug Evaluation 
Unit Intercom 4:3-6. 1975. 
30. EuroQol Quality of Life Group. EuroQol: a new facility for the measurement of 
health-related quality of life. Health Policy;16(3):199-208. 1990. 
31. Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry;154:672-676. 
1989. 
32. Morosini PL, Magliano L, Brambilla L, Ugolini S, Pioli R. Development, reliability 
and acceptability of a new version of the DSM-IV Social and Occupational 
Functioning Assessment Scale (SOFAS) to assess routine social functioning. Acta 
Psychiatr Scand;101:323-329. 2000. 
33. Simpson GM, Angus JWS. A rating scale for extrapyramidal side effects. Acta 
Psychiatr Scand Suppl 212:11-19. 1970. 
34. [NIMH] National Institute of Mental Health. Clinical global impressions. 
Psychopharmacol Bull;21(4):839-843. 1985. 
35. Guy W. ECDEU assessment manual for psychopharmacology. Washington, DC: US 
Department of Health, Education, and Welfare;338:534-537. 1976. 
36. Keefe, R.S., Goldberg, T.E., Harvey, P.D., Gold, J.M., Poe, M.P. & Coughenour, L. 
2004. The Brief Assessment of Cognition in Schizophrenia: reliability, sensitivity, 
and comparison with a standard neurocognitive battery. Schizophrenia Research, 
68(2), 283-297.  
37. Cohen, J. 1992. A Power Primer. Psychological Bulletin, 112(1), 155-159. 
38. Overrall, J.E., Gorham, D.R. The Brief Psychiatric Rating Scale. Psychological 
Reports. 10, 799-812 
39. Leucht, S. et al. (2013). Comparative efficacy and tolerability of 15 antipsychotic 
drugs in schizophrenia: a multiple-treatments meta-analysis. The Lancet, 
382(9896), 951-962.   
 


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ATTACHMENT 1 
Study Procedures Table 
Visit 
1a 
1b 
2 
3a 
Inpatient 
3ba 
Inpatient 
3cb 
Inpatient 
4 
5 
6 
7 
8 
9 
10 
11d /ET 
12 
13 
Day 
 
 
 
-1 to -6 hours 
0 
1 
7 
14 
21 
28 
35 
42 
49 
56 
84 
112 
Visit Window (days since last visit) f 
 
0-30 
0-7 
NA 
NA 
5-9 
5-9 
5-9 
5-9 
5-9 
5-9 
5-9 
5-9 
24-32 
24-32 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCID 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Med/Psych/ Medication History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vitals 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
Ophthalmology Exam 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
ECG (triplicate, 1 min apart) 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
CGI-S&I e 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
BPRS 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PANSS 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
PSP 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
EQ-5D & Quality of Life 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
BACS/Trails B 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
MRI 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
BFCRS 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
AIMS 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
SAS 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
BARS 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 


Stanley Foundation: Fingolimod 
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Visit 
1a 
1b 
2 
3a 
Inpatient 
3ba 
Inpatient 
3cb 
Inpatient 
4 
5 
6 
7 
8 
9 
10 
11d /ET 
12 
13 
Day 
 
 
 
-1 to -6 hours 
0 
1 
7 
14 
21 
28 
35 
42 
49 
56 
84 
112 
Visit Window (days since last visit) f 
 
0-30 
0-7 
NA 
NA 
5-9 
5-9 
5-9 
5-9 
5-9 
5-9 
5-9 
5-9 
24-32 
24-32 
CBC w/ diff 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
CMP 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
TSH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Beta HCG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VZV Titer 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis Panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma Cytokines 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
Magnesium & Calcium 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipid Panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HgbA1c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Toxicology  
X 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
 
Urine Pregnancy Test 
X 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
Adverse Event 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
Concomitant Medication 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
Medication Dispensation 
 
 
 
 
Xc 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
Medication Accountability 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
Telemetry 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
Hourly Blood Pressure 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
a 3b is the first 24 +/- 2 hours post dose 
b 3c will be completed per dosing safety section as outlined in this protocol (if applicable) 
c Initial dose will be administered before 12pm 
d Visit 11 procedures may be split over a 7 day period 
 
e Only CGI-S will be completed at visit 1a 
f: All visits may be split at the discretion of the principal investigator


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ATTACHMENT 2 
 
 
Concomitant Medication Table 
Medication 
Use prior to Visit 4 
Use after Visit 4 
Class 1a antiarrhythmic 
No 
No 
Class 3 antiarrhythmic 
No 
No 
Alpha 2 agonists (eg., Clonidine) 
No 
No 
Alpha-adrenergic blockers (eg, 
doxazosin, terazosin) 
Stable dose, no changes or 
additions 
Stable dose, no changes or 
additions 
Anticoagulants 
No 
No 
Antiemetics (eg., metoclopromide, 
domperidone, other dopamine receptor 
blockers) 
No 
No 
Antiepileptic mood stabilizers 
Stable dose, no changes or 
additions 
Stable dose, no changes or 
additions 
Antihistamines, nonsedating 
Yes 
Yes 
Antihistamines, sedating 
Yesa 
Yesa 
Antineoplastics 
No 
No 
Antipsychotic medications 
Stable dose, no changes or 
additions 
Stable dose, no changes or 
additions 
Antivirals (including trantadine) 
No 
No 
Barbiturates 
No 
No 
Belladonna 
No 
No 
Benzodiazepines 
Yes 
Yes 
Beta 2 agonists (eg, albuterol) 
Yes-Episodic Use Only 
Yes-Episodic Use Only 
Beta blockers 
No 
No 
Bupriopion 
Stable dose, no changes or 
additions 
Stable dose, no changes or 
additions 
Calcium channel blockers (-dipines) 
No 
No 
Cathartics and Laxatives 
Yes-Episodic Use Only 
Yes-Episodic Use Only 
Citalopram (40mg or less) 
Stable dose, no changes or 
additions 
Stable dose, no changes or 
additions 
Corticosteroids (except topical or 
inhaled) 
No 
No 
Decongestants (eg., pseudophedrine) 
No 
No 
Dicyclomine 
Yesa 
Yesa 
Diltiazem 
No 
No 
Digoxin 
No 
No 
Ergotamine, dihydroergotamine 
No 
No 
Gold Compounds 
No 
No 
Herbal medications or Over the Counter 
Medications w/ primary CNS activity 
Conditional Use a  
Conditional Use a 
Hyoscyamine 
No 
No 
Ketamine 
No 
No 
Ketoconazole 
No 
No 
Ketorolac,  
No 
No 
Linezolid 
No 
No 
Lithium 
Stable dose, no changes or 
additions 
Stable dose, no changes or 
additions 
Live attenuated vaccine 
No 
No 
Loop and thiazide diuretics 
Stable dose, no changes or 
additions 
Stable dose, no changes or 
additions 
MAOIs 
No 
No 
Macrolides 
No 
No 
Medroxyprogesterone injections 
Yes 
Yes 
Metaproternal 
No 
No 
Methadone 
No 
No 


Stanley Foundation: Fingolimod 
Version: 02.25.16 
Page 24 of 24 
Methotrexate 
No 
No 
Methyldopa 
No 
No 
Midrin 
Yes 
Yes 
Mineralocorticoids 
No 
No 
Minocycline 
No 
No 
Minoxidil 
No 
No 
Niacin 
No 
No 
Nicotine Replacement 
Yes 
Yes 
Nitrites and nitrates 
No 
No 
Opiates 
No 
Yes 
Phentermine 
No 
No 
Reserpine 
No 
No 
Erectile dysfunction treatments 
No 
No 
Muscle relaxants 
No 
No 
Sleeping medications (zolpidem, etc.) 
Yes 
Yes 
SNRIs 
Stable dose, no changes or 
additions 
Stable dose, no changes or 
additions 
SSRIs 
Stable dose, no changes or 
additions 
Stable dose, no changes or 
additions 
Theophylline 
No 
No 
Tricylic antidepressants 
No 
No 
Triptans 
No 
No 
Varenicline 
No 
No 
Verapamil 
No 
No 
Warfarin 
No 
No 
a Conditional Use: Will be reviewed by the principal investigator on a case by case basis.