Een onderzoek naar de veiligheid en farmacologie van meervoudige doseringen van LY2165766

The drug to be given, LY2165766, is a new investigational compound being
developed to treat schizophrenia. In schizophrenia, the amounts of certain
endogenous compounds that are present in the body including one named dopamine
are thought to be changed in some parts of the brain. LY2165766 and other
similar drugs are thought to help in the treatment of schizophrenia by
correcting these changes. LY2165766 has been observed in animal studies to
behave like drugs already known to be effective in the treatment of
schizophrenia. This new compound is not registered as a drug (experimental).

The purpose of the study is to investigate how well LY2165766 is tolerated. The
study will also investigate how quickly and to what extent the compound is
absorbed and eliminated from the body. This study is not intended to improve
your health, but is necessary for the further development of the compound.

Design:
a randomized, double-blind, placebo-controlled, parallel-group,
multiple-ascending dose study, two-period crossover with two cohorts of ten
healthy male and/or elderly female (postmenopausal/sterilized) subjects each
receiving oral doses of LY2165766 or placebo (eight verum and two placebo) for
seven days

Procedures and assessments
Screening and follow-up:
clinical laboratory, serum prolactin, FSH (females only), vital signs, physical
examination, ECG; at eligibility screening: medical history, alcohol and drug
screen, HBsAg, anti HCV, anti-HIV 1/2; drug screen to be repeated upon admission

Observation period:
one period in clinic from -17 h before drug administration on Day 1 up to 48 h
after drug administration on Day 7

Blood sampling:
for pharmacokinetics of LY2165766 in plasma: pre-dose and 0.5, 1, 2, 3, 4, 8
and 12 h post-dose on Day 1, Days 2, 3 and 5 pre-dose and pre-dose and 0.5, 1,
2, 3 4, 8, 12, 24 and 48 h post-dose on Day 7
for pharmacodynamics of prolactin in serum:
pre-dose and 2, 4, 12 and 24 h post-dose on Days 1 and 7
Safety assessments :
adverse events: throughout the study; clinical laboratory: pre-dose on Day 1, 4
and 9, pre-dose; vital signs: pre-dose and 2 (supine and standing), 4, 8 and 12
h post-dose on Days 1-7; ECG (in triplicate): pre-dose and 1, 4 and 7 h
post-dose on Days 1 to 7
Bioanalysis:
analysis of plasma LY2165766 samples using a validated method by PRA
analysis of serum prolactin samples using clinical laboratory methods by PRA

Study medication Active substance: LY2165766 Activity : dopamine D2, 5-HT2a and 5-HT6 receptor antagonist Indication : schizophrenia Strength : tbd Dosage form: capsule Females : postmenopausal or surgically sterile, 12 months without a menstrual period of perimenopausal women 6 months without a menstrual period and FSH>40 IU/L Treatments Cohort A Period 1: an oral dose of 6 mg LY2165766 or placebo on Days 1-7 in the fasted state Period 2: an oral dose of 16 mg LY2165766 or placebo on Days 1-7 in the fasted state Cohort B Period 1: an oral dose of 10 mg LY2165766 or placebo on Days 1-7 in the fasted state Period 2: an oral dose of tbd mg LY2165766 or placebo on Days 1-7 in the fasted state

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