FASTMAS (New Experimental Medicine Studies: Fast-Fail Trials in Mood and Anxiety Spectrum Disorders) Kappa Opioid Receptor (KOR) Phase 1 Study

This study is an open-label study of two weeks of daily dosing of LY2456302 carried out in
10 healthy volunteers. Subjects will have an initial screening visit where they will have
the opportunity to sign informed consent. Those who choose to do so will undergo a series of
screening tests to determine whether they meet inclusion/exclusion criteria for this study.
Those who qualify will return in 1-7 days for a baseline set of assessments which will
include: having MRI imaging carried out on the first day (structural MRI, fMRI during the
Monetary Incentive Delay Task, and Resting State Connectivity fMRI), and on the second day
having an arterial line placed; undergoing a [11C]-Carfentanil (a synthetic, highly specific
mu opioid receptor (mu-OR) agonist) PET mu opioid receptor occupancy study; undergoing a
LY2879788 ( radioactive biochemical substance (in particular, a ligand) that is used for
diagnosis or for research-oriented study of the receptor systems of the body) PET Kappa
Occupancy Study with a single blood sample taken prior to the scan, a sample during the
scan, and samples taken at 15, 30, 45, 60, 75, 90, and 120 minutes after the scan to
determine whole blood radioactivity, plasma radioactivity, and un-metabolized tracer
fraction over time which are needed to determine the input function to the kinetic model for
analysis of parameter estimation needed to compute receptor occupancy from the PET scan
data; completing a SHAPS; and undergoing a PRT. Note that arterial line placement and serial
blood samples are only needed for the LY2879788 scans because, unlike for [11C]-Carfentanil,
there is no accepted reference region in the brains of humans for this ligand which
necessitates the development of a kinetic model for scan parameter estimation. The next day
subjects will begin taking LY2456302 10 mg daily at 11 am and return to the research unit 6
days later for a safety assessment visit. Subjects will then return to the research unit 7
days later during which they will undergo interval history and safety assessments, take
their medication at 11 am, and then have MRI imaging at 1:30 pm. A blood sample to determine
LY2456302 level will be obtained immediately before and after the MRI imaging session so
that we can determine the relationship between ventral striatal activation during the task
and serum level of LY2456302. They will then return to the research unit the following day
where they will take their last dose of study medication at 11 am and at 1:30 pm will
undergo a [11C]-Carfentanil PET mu opioid receptor occupancy study. A blood sample to
determine LY2456302 level will be obtained immediately before and after the PET imaging
session so that we can determine the relationship between receptor occupancy and serum level
of study drug. The following day subjects will have an arterial line placed and undergo
LY2879788 PET Kappa Occupancy Study at 9:30 am with a single blood sample taken prior to the
scan and samples taken at 15, 30, 45, 60, 75, 90, and 120 minutes after the scan to
determine whole blood radioactivity, plasma radioactivity, and un-metabolized tracer
fraction over time which are needed to determine the input function to the kinetic model for
analysis of parameter estimation needed to compute receptor occupancy from the PET scan
data. A blood sample to determine LY2456302 level will also be obtained immediately before
and after the PET imaging session so that we can compute the relationship between serum
level and receptor occupancy. Subjects will then return 6 days later for a safety assessment
after which their participation in the study will end.

Inclusion Criteria:

- Age 21 through 65 years of age

- Body mass index 19 through 30 lbs/in2

- Reliable and willing to be available for the duration of the study

- Willing and able to give written informed consent to participate

- Able to understand and comply with instructions

- If female of childbearing potential, must agree to use dual methods of contraception
and be willing and able to continue contraception for 6 weeks after the last dose of
study drug. Females using oral contraception must have started using it at least 2
months prior to the Baseline Visit

- If male of childbearing potential, must have undergone surgical sterilization (such
as a vasectomy) or agree to use a condom used with a spermicide during participation
in the study and for 1 month afterward

Exclusion Criteria:

- Any clinically significant abnormality of any of the hematology, clinical, chemistry,
or urine drug tests

- Magnetic resonance imaging contraindications at 3 Tesla (e.g., ferromagnetic implants
or shrapnel or other incompatibilities)

- Any clinically significant abnormality of the 12-lead ECG; QTc (corrected QT)
interval recorded on screening or predose greater than 450 msec

- Any clinically significant history of neurologic disease, cancer, or cardiac,
respiratory, metabolic, hepatic, renal, gastrointestinal (except appendectomy),
dermatological, venereal, hematological disorder or disease

- Any clinically significant history of Axis I psychiatric disorder, or history of
attempted suicide

- History of seeking advice from a physician or counselor for abuse or misuse of
alcohol, non-medical drugs, medicinal drugs or other substance abuse, for example,
solvents

- Any current or previous recreational use of Class A drugs such as opiates, cocaine,
ecstasy, LSD (Lysergic acid diethylamide), and amphetamines (Class B)

- Positive drugs-of-abuse test result at initial exam or at any time during the study

- An alcoholic intake greater than 7 units per week or unwillingness to stop alcohol
consumption for the duration of the study {1 unit = 8 g ethanol (250 mL of beer, 1
glass wine [100 mL], 1 measure spirits [30 mL])}

- Use of prescribed medication within 30 days of the first study day, or
nonprescription medication including herbal remedies except standard dose vitamin
supplements and acetaminophen (up to 4 g/day) within 15 days of the first study drug
administration, or any medication that would need to be continued during the study

- Use of any investigational medication within 3 months prior to the start of this
study or scheduled to receive an investigational drug other than LY2456302 during the
course of this study

- Any smoking of cigarettes or use of any nicotine containing products within the
last month or at any time during the study

- History of blood donation in the last 3 months

- History of severe allergies or multiple adverse drug reactions

- Known hypersensitivity to LY2456302

- Any history of a clinically significant gastrointestinal condition

- Any other condition that in the opinion of the investigator would preclude
participation in the study

- Pregnant or lactating

- History of peptic ulcer disease or gastritis or positive urea breath test