A DOUBLE-BLIND, ASCENDING SINGLE AND MULTIPLE DOSE, SAFETY, TOLERABILITY, PHARMACOKINETIC, PHARMACODYNAMIC AND FOOD EFFECT STUDY OF EVP 6308 IN HEALTHY VOLUNTEERS.

EVP-6308 is a new investigational compound that may eventually be used for the
treatment of schizophrenia. This is the first time that this compound is being
given to humans.

EVP 6308 is a selective phosphodiesterase (PDE) 10A inhibitor being developed
to treat the positive (such as hallucinations and delusions), negative (such as
flattened affect, sexual dysfunction and social withdrawal), and cognitive
symptoms of schizophrenia.

As described in depth in the EVP 6308 Investigator*s Brochure2, there are
several lines of evidence, both neurochemical and behavioral, which suggest
that PDE-10A inhibition may decrease both positive and negative symptoms of
schizophrenia as well as improve cognitive performance. Therefore, PDE10A
inhibitors are potentially a broad spectrum therapy to treat all symptom
domains (positive, negative and cognitive) of schizophrenia.

Primary:
to evaluate the safety and tolerability of EVP-6308 after single and multiple
ascending dose administration in healthy subjects.

Secondary:
to determine the pharmacokinetics of EVP-6308 and select metabolites following
single and multiple oral dose administration of EVP-6308;

to assess the pharmacodynamic effects of EVP-6308 on the central nervous system
using quantitative electroencephalogram analysis, a Digit Symbol Substitution
Test and a subjective mood measurement;

to assess whether the pharmacokinetics of EVP-6308 is affected by food.

A double-blind, randomized, placebo-controlled study, consisting of a single
ascending dose (SAD) with integrated food
effect part, and a multiple ascending dose (MAD) part. In the SAD part,

Cohorts 1 and 2 with 8 subjects (6 subjects on active and 2 on placebo) will be
treated with escalating doses in an alternating panel design with a washout of
at least 14 days between dose administrations. In the first dose cohort, for
risk mitigating purposes, initially 2 subjects (one active, one placebo) will
be dosed and after a 24-hour safety monitoring window, the remainder of the
first cohort will be dosed.
Cohort 3 with 6 subjects (6 subjects on active) will be treated with one dose
level; In the MAD part, 4 groups of 12 subjects (9 subjects on active and 3 on
placebo) will be treated with escalating sequential doses.

Procedures and assessments SAD part:
Screening :
demographics, medical history, clinical laboratory (including clinical
chemistry, hematology and urinalysis), pregancy test
(females), fecal occult blood test, physical examination (including height and
body weight), vital signs (including supine
systolic and diastolic blood pressure, pulse rate, oral body temperature and
respiration rate), 12-lead electrocardiogram
(ECG), screening electroencephalogram (EEG), drug and alcohol screen, HBsAg,
anti HCV, anti-HIV 1/2, adverse events
(AEs), previous and concomitant medication

Observation period:
Groups 1 and 2: three periods in the clinic, each being from Day -1 until 48 h
(Day 3) after drug administration;
Group 3: one period in the clinic from Day -1 until 48 h (Day 3) after drug
administration,
Group 4 - 7: one period in the clinic from Day -1 until 48 h after the last
drug administration on Day 14.

Blood sampling:
During this study less then 450 ml of blood will be drawn. It is anticipated
for Part 1 and 2 that in every period an indwelling canula will be inserted for
most of the blood sampling Day -1 and Day 1, on the other Days blood will be
drawn by direct puncture of the vein. It is anticipated for Part 3 that an
indwelling canula will be used on Days -1 and Day(s) 1, 7, 14. On the other
days blood will be drawn by direct puncture of the vein.

Collection of urine:
Urine will be collected in each Period at pre-dose and in intervals until 24-48
hrs hours after administration of EVP-6308 (thus until Day 3).

Pharmacodynamic tests:
Bond and Lader Visual Analog Scale (VAS): Only in SAD and MAD. This is a
questionnaire where you are asked to rate items related to alertness, calmness
and contentment .SAD: in each Period at set intervals and in MAD: on Days 1 and
14 at set intervals.

Digit Symbol Substitution Test (DSST test): Only in SAD and MAD. The DSST is a
test in which you will asked to substitute figures
by symbols. SAD: in each Period at set intervals and in MAD: on Days 1 and 14
at set intervals.

Screening EEG and Quantitative (q)EEG: Only in MAD. (EEG) will be recorded at
regular intervals using standardized devices on Days 1 and 14.

Safety:
AEs: recorded from the time the Informed Consent Form (ICF) is signed until
completion of the follow up visit; clinical
laboratory (including clinical chemistry, hematology and urinalysis): each
period at 48 h post-dose; vital signs (including
supine systolic and diastolic blood pressure, pulse rate, oral body temperature
and respiration rate): each period at predose
and at 1, 2, 3, 4, 5, 6, 8, 24 and 48 h post-dose; 12-lead ECG: each period at
1, 4, 8, 24, and 48 h post-dose,
physical examination: each period at 48 h post dose.

SAD part:
Group 1 Period 1: a single oral dose of 5 mg EVP 6308 (n=6) or matching placebo
(n=2) under fasted conditions
Period 2: a single oral dose of 20 mg EVP 6308 (n=6) or matching
placebo (n=2) under fasted conditions
Period 3: a single oral dose of 100 mg EVP 6308 (n=6) or matching
placebo (n=2) under fasted conditions
Group 2 Period 1: a single oral dose of 10 mg EVP 6308 (n=6) or matching
placebo (n=2) under fasted conditions
Period 2: a single oral dose of 50 mg EVP 6308 (n=6) or matching
placebo (n=2) under fasted conditions
Period 3: a single oral dose of 200 mg EVP 6308 (n=6) or matching
placebo (n=2) under fasted conditions

FE part:
Group 3 Period 1: a single oral dose of X mg EVP 6308 (n=6) under fasted
conditions
Period 2: a single oral dose of X mg EVP 6308 (n=6) under fed conditions

MAD part:
Group 4 multiple oral doses of 20 mg EVP 6308 (n=9) or matching placebo (n=3)
for 14 days under fasted or fed conditions
Group 5 multiple oral doses of 50 mg EVP 6308 (n=9) or matching placebo (n=3)
for 14 days under fasted or fed conditions
Group 6 multiple oral doses of 100 mg EVP 6308 (n=9) or matching placebo (n=3)
for 14 days under fasted or fed conditions
Group 7 multiple oral doses of 200 mg EVP 6308 (n=9) or matching placebo (n=3)
for 14 days under fasted or fed conditions

Procedures : pain, light bleeding, heamatoma, possibly an infection.