Fingolimod in Schizophrenia Patients

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

Inclusion

- 18 to 65 yrs, able to give informed consent

- DSM IV-TR Diagnosis of schizophrenia or schizoaffective disorder

- Previous and/or current exposure to one of the following antipsychotic medications
(clozapine, olanzapine, risperidone, paliperidone, haloperidol, quetiapine) as defined
by a minimum of 8 weeks in duration greater than or equal to the Food and Drug
Administration (FDA) approved therapeutic range for schizophrenia at the time of study
entry OR previous and/or current exposure to two antipsychotic medications as defined
by a minimum of 4 weeks in duration and greater than or equal to the FDA approved
therapeutic range for schizophrenia at the time of study entry

- willing to participate in a minimum of 1 day of hospitalization

- Clinical stability:

1. CGI-S score of < 4 at randomization AND

2. no exacerbation of illness within 4 weeks prior to randomization, leading to an
intensification of psychiatric care in the opinion of the investigator AND

3. antipsychotic treatment stability for at least 4 weeks prior to randomization

- Female subjects of childbearing potential must test negative for pregnancy at
screening 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

- Subjects must agree not to consume tonic water for the duration of the study and for
two months following cessation of study medication

- Sub-optimally treated positive OR negative symptoms as defined by the Brief
Psychiatric Rating Scale (BPRS):

1. BPRS positive symptom factor (conceptual disorganization, hallucinations,
suspiciousness, unusual thought content) score of > 4 on any one item or a sum >
8 on the factor

2. BPRS negative symptom factor (motor retardation, blunted affect, inappropriate
affect) score of > 4 on any one item or a sum > 6 on the factor

Exclusion

- Subjects who are considered prisoners per the IU Standard Operating Procedures for
Research Involving Human Subjects

- Current acute, serious, or unstable medical conditions

- Clinically significant electrocardiogram abnormality: corrected QT interval >450 msec
(M) or >470 msec (F) prior to randomization OR sinus bradycardia (HR < 50 beats/min)

- Subjects who have experienced the following within the six months prior to study
entry: myocardial infarction, unstable angina, stroke, transient ischemic attach
(TIA), decompensated heart failure requiring hospitalization or Class III/IV heart
failure

- Hypokalemia, hypomagnesemia, or congenital long-QT syndrome

- Known HIV+ status

- Active seizure disorder

- Pregnant or lactating women or women who plan to become pregnant or will be lactating
within two months after cessation of study drug

- Implanted pacemaker, medication pump, vagal stimulator, deep brain stimulator, TENS
unit, ventriculoperitoneal shunt, or other contraindication to undergoing an MRI scan

- Class1a or class 3 antiarrhythmic agents, beta blockers, diltiazem, verapamil,
digoxin, tricyclic antidepressants, warfarin, ketoconazole, ketamine

- Subjects likely to need a live attenuated vaccine during the course of the study or
within two months after stopping study medication

- Subjects with no history of chicken pox or chicken pox vaccination, or with a negative
VZV titer

- Active herpes simplex outbreak, mononucleosis, or zoster

- 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, or severe untreated sleep apnea

- Antineoplastic, immunosuppressive, or immune modulating therapies

- History of macular edema or uveitis

- Known IQ < 70

- Current active fungal or viral infection

- Current DSM IV-TR diagnosis of substance dependence (excluding caffeine and nicotine)

- Positive urine toxicology screen for the following: cocaine, barbiturates,
methamphetamine, opiate, methadone, phencyclidine, or amphetamine prior to
randomization

- Test positive for (1) Hep C virus antibody, (2) Hep B surface antigen (HBsAg) with or
without positive Hep B core total antibody, (3) HIV 1 or 2 antibodies, or (4) Mantoux
tuberculin test.

- Moderate to severe renal impairment as defined by creatinine clearance < 60 ml/min at
screening

- Hepatic impairment as defined by liver transaminases or total bilirubin > 3 × upper
limit of normal

- Subjects considered a high risk for suicidal acts - active suicidal ideation OR any
suicide attempt in 90 days prior to screening

- 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 + 4
weeks) with an investigational depot formulation of an antipsychotic medication

- Subjects who demonstrate overtly aggressive behavior or who are deemed to pose a
homicidal risk in the investigator's opinion